4.6 Article

Estrogen Protects Cardiac Function and Energy Metabolism in Dilated Cardiomyopathy Induced by Loss of Cardiac IRS1 and IRS2

Journal

CIRCULATION-HEART FAILURE
Volume 15, Issue 6, Pages -

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCHEARTFAILURE.121.008758

Keywords

diabetic cardiomyopathy; energy metabolism; estradiol; estrogen; insulin resistance

Funding

  1. National Institutes of Health [R01DK095118, R01 DK120968, R01DK124588, R01DK118334, R01AG064869]
  2. American Diabetes Association [1-15-CD-09]
  3. American Heart Association [BGIA-7880040]
  4. Texas A&M AgriLife Research
  5. US Department of Agriculture National Institute of Food and Agriculture [Hatch 1010958]
  6. American Diabetes Association
  7. Texas AM University

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This study investigates the role of ovaries and ovarian hormone estrogen in cardiac function and energy metabolism. The results show that estrogen can prevent dilated cardiomyopathy, improve cardiac function and energy metabolism, and enhance lifespan. This provides a mechanistic explanation for the gender difference in the incidence of T2D and cardiovascular diseases.
Background: Type 2 diabetes (T2D) is a high-risk factor for incident of cardiovascular diseases. Women at young ages show a reduced incidence of both T2D and cardiovascular diseases compared with men, but these disparities disappear in postmenopausal women versus age-matched men. Thus, ovaries and ovarian hormones, such as estrogen, are expected to protect from T2D and cardiovascular diseases. In this study, we aimed to investigate the role of ovaries and ovarian hormone estrogen in cardiac function and energy metabolism using the cardiac IRS (insulin receptor substrate) 1 and IRS2 double genes knockout mice that mimic cardiac insulin resistance. Methods: Control and heart-specific IRS1/2 double genes knockout mice were treated with placebo or 17 beta-estradiol (E-2) pellets, respectively, through subcutaneous implantation. Female mice were subjected to a bilateral ovariectomy surgery to remove endogenous E-2. The cardiac function and energy metabolism were determined using echocardiography and indirect calorimeter, respectively. Results: All male heart-specific IRS1/2 double genes knockout mice died of heart failure at 6 to 8 weeks as we previously described (Qi et al), but all female heart-specific IRS1/2 double genes knockout mice survived >1 year. Removal of ovaries in heart-specific IRS1/2 double genes knockout female mice resulted in cardiac dysfunction, and ultimately animal death. However, E-2 supplementation prevented the dilated cardiomyopathy, improved cardiac function and energy metabolism, and enhanced lifespan in both male and ovariectomy female mice deficient for cardiac IRS1 and IRS2 genes, largely owing to the activation of Akt (protein kinase B)-Foxo1 (O1 class of forkhead/winged helix transcription factor) signaling cascades. Conclusions: These results show that estrogen protects mice from cardiac insulin resistance-induced diabetic cardiomyopathy. This may provide a fundamental mechanism for the gender difference for the incidence of both T2D and cardiovascular diseases. This study highlights that estrogen signaling could be a potential target for improving cardiac function and energy metabolism in humans with T2D.

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