Volume 36, Issue S1
Pathology
Free Access

Sexual Dimorphism in Control of Heart Failure in Insulin Resistance

Wanbao Yang

Wanbao Yang

Texas A&M University, College Station, TX

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Hui Yan

Hui Yan

Texas A&M University, College Station, TX

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Fenghua Zhou

Fenghua Zhou

Texas A&M University, College Station, TX

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Quan Pan

Quan Pan

Texas A&M University, College Station, TX

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Kimberly Allred

Kimberly Allred

Texas A&M University, College Station, TX

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Clinton Allred

Clinton Allred

Texas A&M University, College Station, TX

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Yuxiang Sun

Yuxiang Sun

Texas A&M University, College Station, TX

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David Threadgill

David Threadgill

Texas A&M University, College Station, TX

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David Dostal

David Dostal

Texas A&M University, College Station, TX

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Carl Tong

Carl Tong

Texas A&M University, College Station, TX

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Shaodong Guo

Shaodong Guo

Texas A&M University, College Station, TX

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This work was supported by National Institutes of Health grants (R01DK095118, R01 DK120968, and R01DK124588), American Diabetes Association Career Development Award (1-15-CD-09), American Heart Association grant (BGIA-7880040), Faculty Start-up funds from Texas A&M AgriLife Research, and USDA National Institute of Food and Agriculture grant (Hatch 1010958) to S.G (PI). This work was also partially supported by the National Institutes of Health (R01DK118334 and R01AG064869) to Y.S. (PI) and S.G. (co-I).

Abstract

The incidence of cardiovascular diseases (CVD) is highly associated with type 2 diabetes (T2D). Women at an early age show reduced incidence of CVD and improved insulin sensitivity compared to men, but these disparities disappear during postmenopausal. Thus, ovary and ovarian hormone, such as estrogen, are expected to protect from these diseases. This study aimed to investigate the role of ovaries and ovarian hormone estrogen in cardiac function and energy metabolism upon loss-of-function of cardiac IRS1 and IRS2 in mice and investigate the underlying mechanisms. We found that all male heart-specific IRS1 and IRS2 double knock-out (H-DKO) mice died of heart failure (HF) at 6-8 weeks with severely impaired energy metabolism. However, all female H-DKO mice survived more than 1 year and showed improvement in energy metabolism. Removal of ovaries in H-DKO female mice led to cardiac dysfunction, disruption of energy metabolism, and ultimately death. However, E2 supplement significantly improved cardiac function, enhanced energy metabolism, and prolonged the lifespan in both male and OVX female H-DKO mice. Finally, we provided evidence that the protective effect of E2 is partially mediated through activation of Akt-Foxo1 signaling in H-DKO heart. These results show that estrogen protects mice from heart insulin resistance induced cardiomyopathy. This study indicates that estrogen signaling could be a potential target to prevent insulin resistance induced heart dysfunction in humans. Estrogen signaling is mediated through estrogen receptors, such as estrogen receptor (ER) α, ERβ, and membrane estrogen receptor (GPER). In the future, we will further decipher the role of estrogen receptors in estrogen mediated protection against cardiac dysfunction during insulin resistance.

This is the full abstract presented at the Experimental Biology meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract.