DUAL ROLE OF STAT3 IN HYPERTENSION‐INDUCED CARDIAC REMODELING

STAT3 has a role in innate immunity and inflammation, but involvement of this transcription factor in cardiac remodeling is controversial. While heart‐targeted STAT3 knockout mice have heart failure with age, unconstrained STAT3 activity was linked to heart dilation in the infarcted myocardium. STAT3‐induced gene expression requires Y705 phosphorylation and is enhanced by S727 phosphorylation. This study assessed the role of STAT3 in heart remodeling induced by hypertension. Four month old SASA mice having a STAT3 S727A mutation that precludes phosphorylation were treated with angiotensin (Ang) II (1000 ng/kg/min) or vehicle for 17 days. Systolic blood pressure (mm Hg) increased in both SASA (169 ± 3) and wild type (WT) mice (166 ± 3) with Ang II. Cardiac levels of inflammatory cytokines were increased with Ang II in both WT and SASA mice, but less so in SASA: Fold increases in IL‐6, TGFβ, VEGF, and MCP1 for WT/SASA mice were respectively: 9/4, 10/4, 3/2, and 16/4. Modest impairments in systolic (ejection fraction & fractional shortening) and diastolic (mitral valve E:A ratio) function were seen with Ang II in both WT and SASA mice, but more so in SASA. Interstitial fibrosis and loss of myofibrillar integrity with Ang II was more pronounced in SASA mice. Our findings show that STAT3 contributes to inflammation of the heart that occurs with hypertension‐induced cardiac remodeling, but also has a role in cardiac protection.