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Rapamycin treatment unmasks a sex-specific pattern of scar expansion of the infarcted rat heart

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Inhibition of the mammalian target of rapamycin (mTOR) with the macrolide rapamycin or pharmacological suppression of K_ATP channel opening translated to scar expansion of the myocardial infarcted (MI) adult female rodent heart. Angelino Calderone tested the hypotheses that rapamycin-mediated scar expansion was sex-specific and that mTOR signaling directly influenced K_ATP channel subunit expression/activity.

Image courtesy of interviewee. April 18, 2024

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This video video is a transcription of a presentation discussing research findings on gender differences in cardiovascular disease, particularly focusing on scar size after myocardial infarction (heart attack). The presenter acknowledges contributors and funding sources for the research, primarily highlighting the role of female sex hormones like estrogen and progesterone in reducing the risk of cardiovascular diseases and the size of myocardial scars in females compared to males.

Key points include:

1. **Protective Factors**: Females generally have a lower risk of cardiovascular diseases and smaller scar sizes after heart attacks compared to age-matched males, potentially due to inherent biological differences and the effects of sex hormones.

2. **Scar Formation Mechanism**: Cardiac myocytes (heart muscle cells) cannot divide or proliferate to heal after injury, leading to permanent scarring, unlike other body tissues that can heal and regenerate.

3. **Research Questions**: A primary focus of the research was to understand why females have smaller scar sizes. Experiments were conducted, including ovariectomy in female rats to study the effects of hormone removal.

4. **Effects of Rapamycin**: The drug rapamycin was used in experiments, and it was found to selectively increase scar size in female rats post-myocardial infarction while having no effect on male rats, suggesting a sex-dependent response to treatment.

5. **mTOR Signaling Pathway and Potassium Channels**: The study connected mTOR signaling with the potassium ATP channels, which are implicated in the protective mechanisms observed in females. Enhanced mTOR activity may result in increased potassium channel activity, influencing cardiac cell survival during ischemic events.

6. **Clinical Implications**: The research suggests a need for more sex-dependent approaches in treating cardiovascular diseases due to the biological differences in how males and females respond to treatment and disease progression.

Overall, the findings underscore the importance of understanding gender differences in cardiovascular health and the potential of hormonal and cellular mechanisms that could inform future treatment strategies.

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Here are several articles that are similar in theme and content to the video regarding gender differences in cardiovascular disease, particularly focusing on the role of sex hormones and biological differences:

1. **Gender Differences in Cardiovascular Disease: A Comprehensive Overview**
- This article explores the physiological differences between men and women regarding cardiovascular health, emphasizing how gender affects risk factors, disease progression, and outcomes following cardiac events.

2. **Hormonal Influence on Cardiovascular Health in Women**
- This publication discusses how female sex hormones, particularly estrogen, influence cardiovascular health, and the implications for treatment strategies in women with heart disease.

3. **The Role of Estrogen in Heart Disease: Mechanisms and Clinical Implications**
- An in-depth look at how estrogen affects cardiovascular physiology, including its potential protective effects against myocardial injury and overall heart health in women.

4. **Understanding Cardiac Scar Formation: Gender Differences in Healing**
- Research focuses on the mechanisms behind scar formation in cardiac tissue, examining how different responses in male and female hearts can lead to variations in outcomes after myocardial infarction.

5. **Sex Differences in the Response to Cardiovascular Treatments: A Focus on mTOR Pathway**
- This article investigates how the mTOR signaling pathway functions differently in males and females, especially in the convideo of drug treatments and their effects on cardiac health and healing.

6. **The Impact of Gender on Cardiac Rehabilitation Outcomes**
- Examines how male and female patients differ in their responses to cardiac rehabilitation programs and the importance of tailored approaches based on gender-based differences.

7. **Myocardial Infarction: Gender-Specific Responses to Treatment**
- A focus on how men and women experience heart attacks differently, including variations in treatment responses and outcomes, with insights into potential gender-specific treatment protocols.

8. **Potassium Channels in Cardiovascular Health: Implications for Gender Differences**
- Discusses the significance of potassium channels in cardiac function and how their regulation may vary between sexes, particularly in the convideo of ischemic injury.

These articles can help provide a broader understanding of the complex interactions between gender and cardiovascular health, emphasizing the importance of considering sex differences in research and clinical practices.

X-TIMESTAMP-MAP:LOCAL=00:00:00.000,MPEGTS=900000

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Okay, before I start to acknowledge the people worked on

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this paper, there's Aya, Maxim Lorenzi,

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my colleagues, Dr.

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Also, it's important to to, to, to, to,

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to indicate the support from the CHR,

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which provide important funding for this research.

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And also like to thank the University of Montreal as well

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as Monte Institute for their support, my ongoing research.

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Thank you again for inviting me, Sam,

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and thank, everyone in your, in your,

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company that has invited me.

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I appreciate it's quite an honor to be here.

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Well, lemme give you a brief context

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before we talk about the study.

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I think it's important to state that

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I think it's been clinically accept

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that females have a lower risk

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of cardiovascular disease versus males age, age match males.

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These include atherosclerosis, hypertension,

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myocardi infarction.

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The hypertension includes, involves high blood pressure,

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atherosclerosis, everyone knows above the plaque and artery.

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Eventually the artery gets blocked

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and tissue that's being perfused by

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that artery unfortunately dies, leads to a heart attack,

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which referred to as myocardial infarction.

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It's interesting is that several studies have shown,

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not all, but several studies have shown that infarct size,

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scar size is smaller in female versus males.

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The question is, why now?

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Why, why does a scar actually occur?

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Very simply is because the adult, cardiac myocyte cell,

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that's response, response for contraction, cannot divide.

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It cannot proliferate. So once you have injury to the heart,

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the cells will die these to a scar

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and their surrounding neighboring cardiac myocytes cannot

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divide or proliferate.

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So they can't help their neighboring dead cell.

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That's why if a scar is always permanent versus when you cut

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your, your finger with a knife, you initially form a scar

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and just same thing as a heart similar to that.

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But then the dermal cells will start to replenish and divide

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and replace the scar with normal tissue.

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You have a normal healing process

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and that's absent in the heart.

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So basically we can say is that it would appear

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that the females have this inherent sex dependent,

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cardio effective phenotype

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or characteristic that provides greater

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protection of cardiovascular disease.

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It's important they both can suffer cardiovascular disease,

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but the risk is just lower in females versus males.

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So the question is, so why are females,

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what females have a smallest scar than males?

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That was, that was one of our fo that was one

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of our primary focus of my research

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and clearly the most important category,

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female sex hormones, estrogen and progesterone.

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And in fact, some numerous studies have shown ally

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experimentally that, you know,

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both hormones will reduce the risk

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of atherosclerosis in myocardi infarction

02:32.515 --> 02:33.635
as well as high blood pressure.

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Um, these data actually refer to post-menopausal women

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after menopause versus disease actually increase

02:40.985 --> 02:42.665
and becomes similar to age match men.

02:43.005 --> 02:44.185
So that there's a role for that.

02:45.005 --> 02:48.785
But the question is, what, why is this occurring?

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Why, why is the scar smaller?

02:51.045 --> 02:53.225
So we did a simple experiment many years ago,

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remove the ovaries from a female rat, all female rat,

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move the ovaries and that reduces level

02:58.745 --> 03:00.645
of progesterone in the normal female rat.

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It's lost, it's gone. And then would just superimposed the,

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a heart attack on the female rat.

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Basically, they would just ude the coronary artery

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completely and saw scar formation.

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And these data showed us no difference

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between a normal female rat versus a rat

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that has no progesterone.

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And some of these data actually reaffirm

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by other studies by other groups.

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So we're not the only one who showed this.

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Now one study does show that

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with the ovary scar size increases.

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Why it is, I don't know. But that's science. Science.

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We have to be, we, we stay, we, we remain objective.

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We can't form a narrative

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where we only form support our own points

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of view nonetheless.

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So the question is, if somebody to the clinical setting,

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we could probably say the following,

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that female SAR hormones may be reduced risk

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of cardiovascular disease or scar or heart attack.

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But once you have a scar, it doesn't play a role.

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So it have two independent events.

03:50.915 --> 03:53.095
So the question is, so we ask the question, well, what,

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what can actually reduce scar size in females versus males?

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So before we did that, another group showed something

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before, before we did in 2006, Johnson, Russell Moore

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and Brown's lab in 2006, publisher physiology showed

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that if you block a channel called potassium a TP channel,

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it led to a larger scar in females following ischemic damage

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means occlusal coronary artery,

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but no effect in males, which is very interesting.

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So they first person to report a sex dependent effect

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protecting females, specifically smaller scar.

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So what's this catastrophe TP channel?

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It's found on the out surface of the,

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cardiac mci, the cell membrane.

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And what it does is that a normal cell doesn't do very much.

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And what the reason for that is the following, a t

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p's a molecule found in the cell and then tri phosphate

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and it blocks activation of this potassium channel.

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So channels never activated,

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only it's only activated open when at TP levels are depleted

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and that occurs following ischemic damage.

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If you have no blood going a certain area,

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those cells become predisposed, the lack

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of oxygen and blood supply.

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A TP levels decrease.

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Potassium channel opens

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and what happens is it results a concept of process versus

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hyperpolarization the cell

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because more electrically, more negative

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because potassium are ly charged, will flow out of the cell.

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Now how does this protect the heart?

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How does this protect the cardiac monocytes from dying?

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Well, it prevents activation other cal,

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channel per the most dependent calcium channel.

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And that channel only activated in the cell becomes

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more positively charged.

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So it prevents calcium entry into the cell.

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And it's been shown that calcium overload,

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the cell kills cardiac monocytes.

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So that's a protective phenotype

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of these potassium A TP channels

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and the consist of two subunits, which are very important.

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The KR 6.2 subunit,

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is the poor form unit basically allows the cells,

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the potassium models to go in and out of the cell.

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You have a regulatory unit called the SUR two A,

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which a regulatory survey which basically could increase

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classroom channel activity.

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So they're the first to show this.

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Some we're not the first, they're the show

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to show this and us.

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In 2009, we did a, we made a serious observation.

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We gave female rat rats rapamycin

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and then superimposed a heart attack on them

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and found a scar size doubled.

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Well, serendipitous, we

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didn't plan to see this just by chance.

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So what is rapamycin? That's the main folks of the study.

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It's a antibiotic goose by bacteria found on Easter island.

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Anti Easter island is the island

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where you have those human statues with overgrown heads.

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So that's Easter Island and the,

06:27.685 --> 06:29.445
and the all is called rapanui.

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I hope I mispronounce that.

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So drug named cut from the island rapamycin.

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And this drug has a number of fascinating effects.

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It's, it's,

06:38.615 --> 06:40.855
immunosuppressed means it reduces the immune response.

06:41.325 --> 06:45.295
It's actually used to prevent the graft tissue rejection in

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patients, for example, kidney transplants.

06:47.215 --> 06:49.215
It's very efficient, it's very efficient in that, in

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that situation also has anti-cancer

06:51.695 --> 06:53.215
effects are very important.

06:53.875 --> 06:55.935
It also increases lifespan longevity.

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Interesting is that several studies should seem suggest

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that females have a better,

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this drugs better effect on females than males,

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which suggests maybe a sex one effect drug also,

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which I'm gonna hopefully can show you that it's actually,

07:09.925 --> 07:12.205
it is truly occurring in more in females than males.

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And so what's the target of rapamycin?

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It's a protein referred to as mTOR,

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the A million targeted of rapamycin.

07:19.725 --> 07:22.565
It's a protein's a kinase, which basically means

07:22.565 --> 07:23.725
that once it's activated,

07:23.725 --> 07:26.695
it recruits other biological events to elicit a,

07:26.815 --> 07:27.855
a biological response.

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So how's it activated? Well, there are amino acids.

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I'm not sure if you know what amino acid is.

07:34.185 --> 07:37.335
Amino acids with protein and they're Syrian three tyrosine.

07:37.335 --> 07:40.055
These amino acids can be phosphorylated, which means,

07:40.055 --> 07:42.455
means you add a phosphate group to this amino acid

07:42.595 --> 07:44.135
and it will increase activity.

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The protein some cases can actually inhibit,

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but in this case, phosphate of mTOR will increase activity.

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And so Dr. Mycin will selectively block the

07:54.535 --> 07:55.575
phosphorylation of mTOR.

07:56.235 --> 07:58.175
So it's a very high specific drug.

07:58.875 --> 08:02.845
Now, interestingly in 2017 I found the paper

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which showed that in pancreatic alpha cells,

08:06.585 --> 08:09.105
which are cells involved in the release since release of,

08:09.445 --> 08:12.025
the glucagon, which plays a role in actually increasing

08:12.025 --> 08:15.555
glucose levels in blood based on the post that effect,

08:15.735 --> 08:20.395
if you block mTOR signaling in these cells, you block active

08:21.215 --> 08:24.115
TP channel an expression of its subunits.

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So there is the al death of our study.

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We show that OMI inhibiting mTOR increased

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scar size in females.

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The paper by Johnson showed the black possibly a TP channel.

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You increased scar size in females.

08:37.275 --> 08:39.685
Therefore now we have a role. Could these two be linked?

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So we basically have three hypotheses.

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We test three specific hypotheses.

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The first hypothesis test was a following, is the scar

08:46.295 --> 08:48.865
smaller in female rats versus male rats?

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In complete occlusion of that, that sort

08:51.645 --> 08:53.445
of sending corona arties, that's they called the LED.

08:53.625 --> 08:55.085
The major RFP is the ventricle.

08:55.545 --> 08:56.965
So a simple question is scar size

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smaller females versus males?

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First? Question two, does rapamycin have the second effect?

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Rapamycin, rapamycin increased scar

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size in females, does it?

09:05.625 --> 09:08.565
The same thing in males, same positive test was rapamycin

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has no effect on scar size in male rats falling

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complete occlusion coronary artery.

09:13.105 --> 09:14.805
And the third hypothesis was that

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mTOR signalling pathway will infect,

09:17.675 --> 09:22.045
will increase ca channel a TP activity, also expression

09:22.045 --> 09:23.045
of protein subunits.

09:23.935 --> 09:25.445
Those are three major hypotheses.

09:25.545 --> 09:28.045
For the first hypothesis we used adult male

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and female rag dolly rats.

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So in between 10

09:31.055 --> 09:36.025
and 12 weeks old what we do is we open the chest, we leg it,

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left venter setting coronary artery completely in both,

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in both the males and females.

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And then after the day later we gave rapamycin or vehicle.

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Vehicle is the liquid we use to dissolve rapamycin.

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So that's an important control. That's very important.

09:48.165 --> 09:49.625
So the controls also have surgery.

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Everything's done exact same way.

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Differences rapamycin in vehicle.

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Uh, we gave 1.5 milligram per kilogram rapamycin

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for six one day after surgery to knew for six days.

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So the seventh day we measured contractile function

10:03.935 --> 10:05.085
using MLR catheter.

10:05.495 --> 10:07.525
Afterwards, afterwards we excise the heart

10:07.585 --> 10:11.415
and we measured scar weight and scar size by telemetry.

10:11.875 --> 10:13.375
And then afterwards we also, another series

10:13.375 --> 10:15.055
of experience looked at the activation

10:15.055 --> 10:16.895
of mTOR signal, which is very important.

10:17.745 --> 10:21.365
And lastly, we used NAL rad ventricular cardiomyocytes

10:21.645 --> 10:23.165
isolated from one day old rad pumps

10:23.465 --> 10:26.605
to look at the relationship between mTOR ANDAs A TP channel

10:26.965 --> 10:28.485
function and protein expression.

10:28.915 --> 10:31.605
Well the first finding which was, which was reassuring, was

10:31.605 --> 10:33.005
that infarct size

10:33.025 --> 10:35.605
or scar size in female rats with treated

10:35.745 --> 10:37.405
as a vehicle was significantly

10:37.405 --> 10:38.965
smaller compared to male rats.

10:39.725 --> 10:42.305
So it was basically twofold, smaller in female versus male.

10:42.305 --> 10:44.465
So scar size, simply different, which is important.

10:44.465 --> 10:46.705
That's important. Then we gave rapid mycin

10:46.705 --> 10:48.265
to adult male rats.

10:48.685 --> 10:50.705
We found no difference in scar size.

10:52.315 --> 10:55.085
Drop mycin selectively affected the scar size in female

10:55.275 --> 10:57.845
rats, not in male rats following complete occlusion

10:57.845 --> 11:00.645
of the coronary artery, which is which which reaffirmed sex

11:00.885 --> 11:02.645
effect, which is really exciting for us.

11:03.685 --> 11:06.785
The third, the third mechanism was mTOR.

11:07.445 --> 11:09.265
So we looked at phospho of mTOR

11:09.565 --> 11:11.385
and we confirmed in female rats,

11:11.565 --> 11:15.025
we actually examined ones amino acid, the serine 2 4 4 8,

11:15.245 --> 11:16.705
and the mTOR and protein.

11:17.125 --> 11:19.545
It was clearly inhibited in both normal MI rats.

11:20.245 --> 11:22.335
However, in male rats we saw no inhibition

11:22.355 --> 11:25.945
of the phosphol state, which which also shows that

11:26.205 --> 11:28.185
by MI effects males differently from females.

11:28.185 --> 11:29.545
But we don't know why that's occurring.

11:30.025 --> 11:31.985
I can peculate on that, but I I can't give you

11:31.985 --> 11:33.025
a convincing answer right now.

11:33.935 --> 11:37.265
I'll say afterwards we want to reaffirm the role

11:37.265 --> 11:38.705
of mTOR class, TP channel.

11:38.725 --> 11:40.345
So the first thing we did was wanted to confirm

11:40.735 --> 11:42.265
that the child expressed similar male

11:42.265 --> 11:44.425
and female rats in normal female rats.

11:44.525 --> 11:46.665
So with the subunits KR 6.2

11:46.665 --> 11:48.505
and SUR two a, an expression

11:48.505 --> 11:50.745
of both s were similar in male and female rats.

11:50.815 --> 11:51.905
There's no difference there.

11:52.085 --> 11:54.965
So that tells us that if it's mTOR coupled

11:54.965 --> 11:58.285
to this TP channel, it must be a greater activation rate

11:58.285 --> 11:59.565
or faster rapid recruitment

11:59.565 --> 12:01.485
of the channels in females versus males

12:01.595 --> 12:03.245
because a similar level of expression.

12:03.505 --> 12:05.245
So the question you have to ask is why is it

12:05.245 --> 12:06.365
not infected in male rats?

12:06.685 --> 12:08.405
'cause they both, they express the same amount of protein.

12:08.595 --> 12:12.995
It's channel also. So it's, we, we don't know.

12:13.175 --> 12:15.435
So that's just the way it is now. It's a little confusing.

12:15.435 --> 12:17.395
So it's, but that's, but I had to reaffirm

12:17.395 --> 12:19.235
that finding without that finding.

12:19.315 --> 12:20.315
I, I can only speculate.

12:20.315 --> 12:21.995
So I, I'm, I'm glad about that finding.

12:22.425 --> 12:25.275
Then last question we asked was, okay, does mTOR couple

12:25.975 --> 12:29.275
to express TP channel expression and furthermore activity?

12:29.895 --> 12:31.235
So first thing we did was took needle,

12:31.235 --> 12:32.355
direct cardiac monocytes.

12:32.355 --> 12:35.355
We confirmed mTOR activation that's being activated.

12:35.355 --> 12:38.315
It's being phosphorylated. The downstream events coupled

12:38.315 --> 12:41.635
to mTOR being activated also we gave rapamycin

12:41.765 --> 12:43.235
completely blocked the response.

12:43.235 --> 12:45.195
Everything was inhibited. mTOR is being inhibited.

12:45.645 --> 12:46.875
Those experiences, we found the

12:46.875 --> 12:47.915
following is really exciting.

12:48.495 --> 12:52.155
We found that mTOR increased expression of the SU two A

12:52.335 --> 12:53.875
of the potassium a TP channel.

12:54.515 --> 12:56.295
And that's important because this protein

12:56.835 --> 12:57.855
can influence activity.

12:58.885 --> 13:01.665
So higher expression of SUR two a higher potassium

13:01.665 --> 13:02.825
channel, a TP activity.

13:03.245 --> 13:04.425
So, which is really exciting.

13:04.565 --> 13:05.865
So we made a link, it exists

13:06.645 --> 13:08.835
and then we looked at biological activity

13:08.935 --> 13:10.995
or the current, which is very important.

13:11.495 --> 13:13.155
So what we did was we took these monocytes,

13:13.155 --> 13:15.645
removed a TP completely with the calcium

13:15.705 --> 13:16.925
and looked at potassium current.

13:17.305 --> 13:21.085
We confirmed the current using the g olamide.

13:21.085 --> 13:23.525
It's an inhibitor of the pharmac of the potassium.

13:23.525 --> 13:24.965
At TP channel was clearly suppressed,

13:24.965 --> 13:27.205
which is convinced it's reassuring.

13:27.555 --> 13:29.565
Unfortunately, when we activate mTOR,

13:30.025 --> 13:32.445
we saw no change in testing in child P activity.

13:33.165 --> 13:35.625
The current didn't change give rapamycin.

13:35.805 --> 13:36.825
We saw no effect either.

13:38.075 --> 13:39.335
So we were a little disheartened by that.

13:39.995 --> 13:42.135
But I mean, it's, it, it is what it's, that's the finding.

13:42.135 --> 13:44.415
We have, I think, I think the most important clue

13:44.415 --> 13:47.575
of the following, that at least in the female rat model,

13:48.505 --> 13:50.285
we have two systems that protect the heart.

13:50.855 --> 13:54.225
Potassium, a P channel and rapamycin mTOR signaling pathway.

13:54.655 --> 13:56.745
They both appear to play an important role in,

13:56.885 --> 13:58.705
in limiting scar expansion,

13:58.705 --> 14:00.425
falling ischemic damage, which is very important.

14:01.135 --> 14:03.395
Uh, number two, we show

14:03.395 --> 14:06.675
that the female heart has a smallest score versus male reps.

14:06.695 --> 14:08.925
So that's important. Also three,

14:08.925 --> 14:09.925
which is also very important.

14:09.925 --> 14:13.005
We did show link with mTOR and potassium TP channel.

14:13.475 --> 14:15.165
They are linked in cardiac monocytes.

14:15.165 --> 14:17.845
We can induce increased by SU two A subunit.

14:18.025 --> 14:20.855
So there's a link there where an important limitation is

14:20.855 --> 14:22.055
that we didn't, maybe didn't use the right cardiac

14:22.245 --> 14:24.435
monocytes using neonatal cells.

14:24.435 --> 14:26.715
The reason weal cells, because we used to isolate, used

14:26.715 --> 14:29.155
to work with, it would've been better if you would've used

14:29.155 --> 14:31.035
the doc cardiac me sites from the region

14:31.765 --> 14:32.955
where it's ischemic.

14:33.925 --> 14:35.025
But that's not easy to isolate.

14:35.025 --> 14:37.735
It's problematic and you don't get many cells.

14:37.835 --> 14:38.855
We don't know if they're functional.

14:38.855 --> 14:40.455
It's, it's a hit or miss

14:40.475 --> 14:41.815
and we just didn't have to take that chance.

14:41.915 --> 14:44.345
It would've been too much work. Nonetheless,

14:44.375 --> 14:45.905
that would've been ideal, which we didn't do.

14:46.565 --> 14:47.655
It's limitation of the study.

14:48.255 --> 14:50.145
However, an important factor is,

14:50.885 --> 14:54.745
Uh, there's a prevailing view in clinically that there has

14:54.745 --> 14:56.505
to be more sex dependent approach

14:56.505 --> 14:57.865
to treating cardiovascular disease.

14:58.765 --> 15:00.485
I mean, obviously men and women are different. We know that.

15:00.945 --> 15:02.445
But they're different in many ways other than

15:02.445 --> 15:03.965
simply visually or sexually.

15:04.155 --> 15:05.245
They respond differently to the disease,

15:05.245 --> 15:06.325
they respond differently to drugs.

15:06.865 --> 15:09.285
It has to be taken consideration when treating patients,

15:09.285 --> 15:10.245
either male or female.

00:00 - Okay, before I start to acknowledge the people worked on this paper, there's Aya, Maxim Lorenzi, my colleagues, Dr. Also, it's important to to, to, to, to, to indicate the support from the CHR, which provide important funding for this research.

00:20 - And also like to thank the University of Montreal as well as Monte Institute for their support, my ongoing research. Thank you again for inviting me, Sam, and thank, everyone in your, in your, company that has invited me. I appreciate it's quite an honor to be here. Well, lemme give you a brief context before we talk about the study. I think it's important to state that I think it's been clinically accept

00:37 - that females have a lower risk of cardiovascular disease versus males age, age match males. These include atherosclerosis, hypertension, myocardi infarction. The hypertension includes, involves high blood pressure, atherosclerosis, everyone knows above the plaque and artery. Eventually the artery gets blocked and tissue that's being perfused by that artery unfortunately dies, leads to a heart attack, which referred to as myocardial infarction.

01:04 - It's interesting is that several studies have shown, not all, but several studies have shown that infarct size, scar size is smaller in female versus males. The question is, why now? Why, why does a scar actually occur? Very simply is because the adult, cardiac myocyte cell, that's response, response for contraction, cannot divide. It cannot proliferate. So once you have injury to the heart, the cells will die these to a scar and their surrounding neighboring cardiac myocytes cannot

01:32 - divide or proliferate. So they can't help their neighboring dead cell. That's why if a scar is always permanent versus when you cut your, your finger with a knife, you initially form a scar and just same thing as a heart similar to that. But then the dermal cells will start to replenish and divide and replace the scar with normal tissue. You have a normal healing process and that's absent in the heart. So basically we can say is that it would appear

01:56 - that the females have this inherent sex dependent, cardio effective phenotype or characteristic that provides greater protection of cardiovascular disease. It's important they both can suffer cardiovascular disease, but the risk is just lower in females versus males. So the question is, so why are females, what females have a smallest scar than males? That was, that was one of our fo that was one of our primary focus of my research

02:19 - and clearly the most important category, female sex hormones, estrogen and progesterone. And in fact, some numerous studies have shown ally experimentally that, you know, both hormones will reduce the risk of atherosclerosis in myocardi infarction as well as high blood pressure. these data actually refer to post-menopausal women after menopause versus disease actually increase and becomes similar to age match men.

02:43 - So that there's a role for that. But the question is, what, why is this occurring? Why, why is the scar smaller? So we did a simple experiment many years ago, remove the ovaries from a female rat, all female rat, move the ovaries and that reduces level of progesterone in the normal female rat. It's lost, it's gone. And then would just superimposed the, a heart attack on the female rat. Basically, they would just ude the coronary artery

03:07 - completely and saw scar formation. And these data showed us no difference between a normal female rat versus a rat that has no progesterone. And some of these data actually reaffirm by other studies by other groups. So we're not the only one who showed this. Now one study does show that with the ovary scar size increases. Why it is, I don't know. But that's science. Science.

03:28 - We have to be, we, we stay, we, we remain objective. We can't form a narrative where we only form support our own points of view nonetheless. So the question is, if somebody to the clinical setting, we could probably say the following, that female SAR hormones may be reduced risk of cardiovascular disease or scar or heart attack. But once you have a scar, it doesn't play a role. So it have two independent events.

03:50 - So the question is, so we ask the question, well, what, what can actually reduce scar size in females versus males? So before we did that, another group showed something before, before we did in 2006, Johnson, Russell Moore and Brown's lab in 2006, publisher physiology showed that if you block a channel called potassium a TP channel, it led to a larger scar in females following ischemic damage means occlusal coronary artery, but no effect in males, which is very interesting. So they first person to report a sex dependent effect

04:23 - protecting females, specifically smaller scar. So what's this catastrophe TP channel? It's found on the out surface of the, cardiac mci, the cell membrane. And what it does is that a normal cell doesn't do very much. And what the reason for that is the following, a t p's a molecule found in the cell and then tri phosphate and it blocks activation of this potassium channel. So channels never activated, only it's only activated open when at TP levels are depleted

04:50 - and that occurs following ischemic damage. If you have no blood going a certain area, those cells become predisposed, the lack of oxygen and blood supply. A TP levels decrease. Potassium channel opens and what happens is it results a concept of process versus hyperpolarization the cell because more electrically, more negative because potassium are ly charged, will flow out of the cell.

05:14 - Now how does this protect the heart? How does this protect the cardiac monocytes from dying? Well, it prevents activation other cal, channel per the most dependent calcium channel. And that channel only activated in the cell becomes more positively charged. So it prevents calcium entry into the cell. And it's been shown that calcium overload, the cell kills cardiac monocytes. So that's a protective phenotype

05:34 - of these potassium A TP channels and the consist of two subunits, which are very important. The KR 6.2 subunit, is the poor form unit basically allows the cells, the potassium models to go in and out of the cell. You have a regulatory unit called the SUR two A, which a regulatory survey which basically could increase classroom channel activity. So they're the first to show this. Some we're not the first, they're the show

05:57 - to show this and us. In 2009, we did a, we made a serious observation. We gave female rat rats rapamycin and then superimposed a heart attack on them and found a scar size doubled. Well, serendipitous, we didn't plan to see this just by chance. So what is rapamycin? That's the main folks of the study. It's a antibiotic goose by bacteria found on Easter island. Anti Easter island is the island

06:22 - where you have those human statues with overgrown heads. So that's Easter Island and the, and the all is called rapanui. I hope I mispronounce that. So drug named cut from the island rapamycin. And this drug has a number of fascinating effects. It's, it's, immunosuppressed means it reduces the immune response. It's actually used to prevent the graft tissue rejection in patients, for example, kidney transplants.

06:47 - It's very efficient, it's very efficient in that, in that situation also has anti-cancer effects are very important. It also increases lifespan longevity. Interesting is that several studies should seem suggest that females have a better, this drugs better effect on females than males, which suggests maybe a sex one effect drug also, which I'm gonna hopefully can show you that it's actually, it is truly occurring in more in females than males.

07:12 - And so what's the target of rapamycin? It's a protein referred to as mTOR, the A million targeted of rapamycin. It's a protein's a kinase, which basically means that once it's activated, it recruits other biological events to elicit a, a biological response. So how's it activated? Well, there are amino acids. I'm not sure if you know what amino acid is. Amino acids with protein and they're Syrian three tyrosine.

07:37 - These amino acids can be phosphorylated, which means, means you add a phosphate group to this amino acid and it will increase activity. The protein some cases can actually inhibit, but in this case, phosphate of mTOR will increase activity. And so Dr. Mycin will selectively block the phosphorylation of mTOR. So it's a very high specific drug. Now, interestingly in 2017 I found the paper which showed that in pancreatic alpha cells,

08:06 - which are cells involved in the release since release of, the glucagon, which plays a role in actually increasing glucose levels in blood based on the post that effect, if you block mTOR signaling in these cells, you block active TP channel an expression of its subunits. So there is the al death of our study. We show that OMI inhibiting mTOR increased scar size in females. The paper by Johnson showed the black possibly a TP channel. You increased scar size in females.

08:37 - Therefore now we have a role. Could these two be linked? So we basically have three hypotheses. We test three specific hypotheses. The first hypothesis test was a following, is the scar smaller in female rats versus male rats? In complete occlusion of that, that sort of sending corona arties, that's they called the LED. The major RFP is the ventricle. So a simple question is scar size smaller females versus males?

08:58 - First? Question two, does rapamycin have the second effect? Rapamycin, rapamycin increased scar size in females, does it? The same thing in males, same positive test was rapamycin has no effect on scar size in male rats falling complete occlusion coronary artery. And the third hypothesis was that mTOR signalling pathway will infect, will increase ca channel a TP activity, also expression of protein subunits.

09:23 - Those are three major hypotheses. For the first hypothesis we used adult male and female rag dolly rats. So in between 10 and 12 weeks old what we do is we open the chest, we leg it, left venter setting coronary artery completely in both, in both the males and females. And then after the day later we gave rapamycin or vehicle. Vehicle is the liquid we use to dissolve rapamycin. So that's an important control. That's very important.

09:48 - So the controls also have surgery. Everything's done exact same way. Differences rapamycin in vehicle. we gave 1.5 milligram per kilogram rapamycin for six one day after surgery to knew for six days. So the seventh day we measured contractile function using MLR catheter. Afterwards, afterwards we excise the heart and we measured scar weight and scar size by telemetry. And then afterwards we also, another series

10:13 - of experience looked at the activation of mTOR signal, which is very important. And lastly, we used NAL rad ventricular cardiomyocytes isolated from one day old rad pumps to look at the relationship between mTOR ANDAs A TP channel function and protein expression. Well the first finding which was, which was reassuring, was that infarct size or scar size in female rats with treated as a vehicle was significantly

10:37 - smaller compared to male rats. So it was basically twofold, smaller in female versus male. So scar size, simply different, which is important. That's important. Then we gave rapid mycin to adult male rats. We found no difference in scar size. Drop mycin selectively affected the scar size in female rats, not in male rats following complete occlusion of the coronary artery, which is which which reaffirmed sex effect, which is really exciting for us.

11:03 - The third, the third mechanism was mTOR. So we looked at phospho of mTOR and we confirmed in female rats, we actually examined ones amino acid, the serine 2 4 4 8, and the mTOR and protein. It was clearly inhibited in both normal MI rats. However, in male rats we saw no inhibition of the phosphol state, which which also shows that by MI effects males differently from females. But we don't know why that's occurring.

11:30 - I can peculate on that, but I I can't give you a convincing answer right now. I'll say afterwards we want to reaffirm the role of mTOR class, TP channel. So the first thing we did was wanted to confirm that the child expressed similar male and female rats in normal female rats. So with the subunits KR 6.2 and SUR two a, an expression of both s were similar in male and female rats.

11:50 - There's no difference there. So that tells us that if it's mTOR coupled to this TP channel, it must be a greater activation rate or faster rapid recruitment of the channels in females versus males because a similar level of expression. So the question you have to ask is why is it not infected in male rats? 'cause they both, they express the same amount of protein. It's channel also. So it's, we, we don't know.

12:13 - So that's just the way it is now. It's a little confusing. So it's, but that's, but I had to reaffirm that finding without that finding. I, I can only speculate. So I, I'm, I'm glad about that finding. Then last question we asked was, okay, does mTOR couple to express TP channel expression and furthermore activity? So first thing we did was took needle, direct cardiac monocytes. We confirmed mTOR activation that's being activated.

12:35 - It's being phosphorylated. The downstream events coupled to mTOR being activated also we gave rapamycin completely blocked the response. Everything was inhibited. mTOR is being inhibited. Those experiences, we found the following is really exciting. We found that mTOR increased expression of the SU two A of the potassium a TP channel. And that's important because this protein can influence activity.

12:58 - So higher expression of SUR two a higher potassium channel, a TP activity. So, which is really exciting. So we made a link, it exists and then we looked at biological activity or the current, which is very important. So what we did was we took these monocytes, removed a TP completely with the calcium and looked at potassium current. We confirmed the current using the g olamide.

13:21 - It's an inhibitor of the pharmac of the potassium. At TP channel was clearly suppressed, which is convinced it's reassuring. Unfortunately, when we activate mTOR, we saw no change in testing in child P activity. The current didn't change give rapamycin. We saw no effect either. So we were a little disheartened by that. But I mean, it's, it, it is what it's, that's the finding. We have, I think, I think the most important clue

13:44 - of the following, that at least in the female rat model, we have two systems that protect the heart. Potassium, a P channel and rapamycin mTOR signaling pathway. They both appear to play an important role in, in limiting scar expansion, falling ischemic damage, which is very important. number two, we show that the female heart has a smallest score versus male reps. So that's important. Also three, which is also very important.

14:09 - We did show link with mTOR and potassium TP channel. They are linked in cardiac monocytes. We can induce increased by SU two A subunit. So there's a link there where an important limitation is that we didn't, maybe didn't use the right cardiac monocytes using neonatal cells. The reason weal cells, because we used to isolate, used to work with, it would've been better if you would've used the doc cardiac me sites from the region where it's ischemic.

14:33 - But that's not easy to isolate. It's problematic and you don't get many cells. We don't know if they're functional. It's, it's a hit or miss and we just didn't have to take that chance. It would've been too much work. Nonetheless, that would've been ideal, which we didn't do. It's limitation of the study. However, an important factor is, there's a prevailing view in clinically that there has

14:54 - to be more sex dependent approach to treating cardiovascular disease. I mean, obviously men and women are different. We know that. But they're different in many ways other than simply visually or sexually. They respond differently to the disease, they respond differently to drugs. It has to be taken consideration when treating patients, either male or female.

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