Differential PI3K signal transduction in obesity-associated cardiac hypertrophy and response to ischemia

Obesity (Silver Spring). 2015 Jan;23(1):90-9. doi: 10.1002/oby.20888. Epub 2014 Aug 30.

Abstract

Objective: Elevated insulin and inflammatory cytokine levels in obesity may chronically activate signaling pathways regulating cardiac growth and contractility. Our aim was to examine the effect of obesity on cardiac PI3K isoform and Akt activation during left ventricular (LV) hypertrophy and heart failure.

Methods: Wild-type mice were fed normal chow or high-fat diet (HFD) for 2, 4, or 6 months. A subset of mice was subjected to chronic myocardial ischemia (MI).

Results: Echocardiography revealed a progressive increase in LV mass, wall thickness, and diameters in obese mice. Systolic pump function was not impaired. Increased cardiac levels of PI3Kγ, phosphorylated Akt, GSK3β, and Epac were observed after HFD for 2 months but gradually declined and were normal or reduced after 6 months, paralleled by elevated PP2A and SOCS3 levels. MI resulted in heart failure, independent of obesity, but compensatory LV hypertrophy was absent in obese mice. Histochemical analyses revealed similar increases in cardiac fibrosis, inflammation, apoptosis, and angiogenesis in lean and obese mice.

Conclusions: Our findings suggest that activation of Akt initially contributes to cardiac hypertrophy and that chronic metabolic and inflammatory stimulation and overexpression of inhibitory mediators decrease PI3Kγ-mediated Akt signaling and blunt compensatory hypertrophy after MI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blood Pressure
  • Cardiomegaly / diagnostic imaging
  • Cardiomegaly / etiology
  • Cardiomegaly / metabolism*
  • Chronic Disease
  • Diet, High-Fat
  • Echocardiography
  • Female
  • Heart Rate
  • Hypertrophy, Left Ventricular / diagnostic imaging
  • Hypertrophy, Left Ventricular / etiology
  • Hypertrophy, Left Ventricular / metabolism*
  • Hypertrophy, Left Ventricular / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Myocardial Ischemia / diagnostic imaging
  • Myocardial Ischemia / etiology
  • Myocardial Ischemia / metabolism*
  • Obesity / complications
  • Obesity / diagnostic imaging
  • Obesity / metabolism*
  • Obesity / physiopathology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Signal Transduction

Substances

  • Phosphatidylinositol 3-Kinases