Abstract 16644: TGF-β/Smad3 Activation in the Diabetic Mouse Heart Induces Fibrotic Cardiac Remodeling and Diastolic Dysfunction While Protecting From Excessive Matrix Degradation and Preventing the Development of Systolic Dysfunction

Abstract

Hypertrophy, fibrosis and diastolic dysfunction are the main characteristics of diabetic cardiomyopathy. Our study examines the role of the pro-fibrotic TGF-β/Smad3 pathway in the diabetic heart using leptin resistant db/db mice. db/db mice developed diabetes and severe obesity and had marked elevation in circulating leptin levels. Despite exhibiting central leptin resistance (resulting in hyperphagia), db/db mice expressed a functional short-form leptin receptor in the myocardium. db/db hearts had concentric hypertrophy and diastolic dysfunction; systolic function was preserved. Collagen deposition was increased in db/db hearts; fibrotic changes were preceded by cytokine and chemokine induction and by activation of Smad3 signaling. In vitro, db/db cardiac fibroblasts exhibited marked upregulation of cytokines, chemokines and MMPs upon leptin stimulation indicating full responsiveness to the actions of leptin. In order to examine the role of Smad3 in morphology and function of the db/db heart we generated db/db Smad3 mutant mice. db/db Smad3 -/- mice exhibited high early mortality; the causes of early death are under investigation. In contrast, db/db Smad3 +/- heterozygotes (het) had similar survival curves, comparable weight gain and fat content with db/db Smad3+/+ animals. However, het mice had significant ventricular dilation (LVEDV, db/db: 82.9+4.7 vs. het: 125.6+6.4; p<0.01) accompanied by systolic dysfunction (FS, db/db: 42.8+2.9 vs. het: 29.1+2.7; p<0.01). Diastolic dysfunction, assessed through P:V loop analysis, was attenuated in het animals. In contrast, non-obese het mice had comparable chamber dimensions and function with WT Smad3 +/+ animals. The dilative remodeling, systolic dysfunction and attenuated diastolic dysfunction observed in obese diabetic het mice were associated with reduced collagen deposition, and increased MMP activity. Cardiac function and geometry in the diabetic heart are dependent on a balance between leptin and Smad3-mediated actions. Attenuation of Smad3 signaling in db/db mice prevents fibrosis and diastolic dysfunction, but also allows unopposed pro-inflammatory leptin-mediated effects resulting in impaired matrix preservation, chamber dilation and systolic dysfunction.