Abstract 5277: Cardiac STAT3 Protects the Heart from Deterioration of Left Ventricular Function, Maladaptive Cardiac Remodeling, and Increased Mortality under Chronic β-Adrenergic Stress
Objectives: Activation of STAT3 in the myocardium exerts cardioprotective effects in response to pathophysiological stress such as ischemia. STAT3 expression is reduced in endstage failing human hearts. We explored the relevance of STAT3 for adaptive mechanisms in response to neurohumoral activation in the heart.
Methods: Male mice (age 3 months) with a cardiomyocyte-restricted knockout of STAT3 (αMHC-Cretg/+;STAT3flox/flox, STAT3-KO) and wildtype mice (STAT3flox/flox, WT) were treated with sub-pressure doses of angiotensin II (AngII: 0.15mg/kgBW/day) or phenylephrine (PE: 0.1mg/kgBW/day), or with isoproterenol (Iso: 60mg/kgBW/day) via osmotic minipumps for 2 weeks. Serial high-resolution echocardiography was performed at 3, 7, 14 days; hemodynamic measurements and histochemical analyses were carried out after 7 and 14 days.
Results: Baseline cardiac function and dimensions were comparable between WT and STAT3-KO. Microarray analysis showed a reduced expression of calcium channels and calcium binding proteins (e.g. Cacna1e -13,22x, Ryr3 -4,87x, Cabp1 -2,43x) in STAT3-KO hearts under basal conditions. AngII and PE treatment did not alter blood pressure, cardiac function and survival and evoked similar hypertrophic responses in WT and STAT3-KO. In contrast, β-adrenergic stimulation with Iso induced excessive inotropic (%FS: +103% vs +68%, P<0.05) and dromotropic (heart rate: +44% vs +23%, P<0.05) responses in the early stage (3 days) with subsequent progressive LV dysfunction and dilation (STAT3-KO: FAC 27%, LVEDD 5,2mm vs. WT: FAC 61%, LVEDD 4,3mm; p<0,05) and increased mortality (STAT3-KO: 70% vs. WT: 10%; p<0,01) in STAT3-KO mice but not in WT mice. Iso induced a similar increase in cardiomyocyte apoptosis in both genotypes. Histological analysis showed a marked increase in inflammatory infiltrates (CD45 positive cells) and endomyocardial fibrosis in STAT3-KO compared with WT.
Conclusion: Lack of STAT3 in cardiomyocytes reduces expression of calcium channels and calcium binding proteins and is associated with exaggerated acute response and progressive adverse LV remodeling in response to chronic β-adrenergic stimulation. This data indicate a specific role of STAT3 in the protection of the heart against beta-adrenergic stress.