Abstract 110: Importance of the C-Terminal Transactivation Domain of STAT3 in Hypertension-Induced Cardiac Hypertrophy
Signal transducer and activator of transcription 3 (STAT3) is known to have protective effects in the heart in acute oxidative stress such as myocardial infarction; however, the role of STAT3 in the heart in response to chronic stress, such as hypertension, is not defined. Here, we assessed the importance of STAT3 on cardiac remodeling post abdominal aortic constriction (AAC) using mice expressing a STAT3 protein lacking the transactivation domain (TAD; aa701-732) selectively in cardiomyocytes (cm-STAT3Δ). Loss of the TAD region impairs both the mitochondrial and transcriptional actions of STAT3. Both WT and cm-STAT3Δ mice developed hypertension to a comparable extent. However, cm-STAT3Δ mice exhibited a significant (p < 0.01) decline in ejection fraction (58.3 ± 4.7 to 24.2 ± 3.6, n=4) and fractional shortening (30.8 ± 3.4 to 11.2 ± 1.7, n=4) over 28 days following AAC, while WT mice exhibited a compensatory response in EF (58.6 ± 3.2 to 59.4 ± 6.0) and FS (30.7 ± 2.1 to 33.0 ± 2.8). Notably, hearts of cm-STAT3Δ exhibited a marked increase in diastolic left ventricular internal diameter (LVIDd), symptomatic of eccentric hypertrophy and dilated cardiomyopathy. In contrast, the pattern of change in LVIDd for WT mice was consistent with concentric remodeling. Banding caused comparable increases in heart to body weight ratios in WT (4.1 ± 0.1 to 6.4 ± 1.0) and cm-STAT3Δ (4.0 ± 0.1 to 7.2 ± 0.6) mice, although on average the increase was larger in cm-STAT3Δ mice. Interestingly, we also found that miR-199a-5p levels were only moderately higher (36%) after AAC in the ventricles of cm-STAT3Δ mice vs. wild type hearts as compared to cardiomyocyte-targeted STAT3 KO mice in which the DNA binding domain of STAT3 is deleted. miR-199a-5p is a known inhibitor of peroxisome proliferator-activated receptor delta (PPARδ) expression and mitochondrial fatty acid oxidation in the heart. These new findings emphasize the distinctive and important role of the C-terminus of STAT3 in the hypertrophic response of the heart to hypertension and the progression to heart failure.
Author Disclosures: F.A. Zouein: None. C. Zgheib: None. J.M. do Carmo: None. R. Vaka: None. R. Altara: None. M. Kurdi: None. G. Booz: None.
- © 2015 by American Heart Association, Inc.