Abstract 13963: Smooth Muscle Cells Promote Hypertensive Cardiac Hypertrophy Through Sox6 Signaling

Abstract

Introduction: Hypertension is the predominant risk factor for mortality. To compensate for pressure overload and reduce stress on the left ventricle, cardiomyocytes become hypertrophic. Recently, several laboratories have suggested that cardiomyocyte hypertrophy is regulated by factors released from adjacent non-cardiomyocytes. Stretching induced in cultured cardiomyocytes, fibroblasts, endothelial cells and smooth muscle cells (SMCs) to secrete factors which cause cardiomyocyte hypertrophy. We hypothesized that cardiac SMCs promote hypertensive cardiac hypertrophy through molecular signals controlled by the transcription factor Sox6. Methods: We used a SMCs tamoxifen inducible Sox6 knock out mice (Myh11 CreERT2 /Sox6 fl/fl -Sox6KO) to define if Sox6 was involved in hypertensive cardiomyopathy. Hypertension was induced by Angiotensin II (Ang II-1000 ng/kg/min x 28 days) infusion after tamoxifen. Cardiac function was measured by ultrasound; cardiomyocyte shape was defined by staining tissue sections with cardiac troponin-T and wheat germ agglutinin; and blood pressure was determined by tail cuff. Results: Ang II induced hypertension in Sox6KO and the Myh11 CreERT2 /Sox6 wt/wt (Myh11 CreERT2 -wild type for Sox6) (SBP mm Hg, 150 vs. 153, SEM= 11 n=3-4). The Myh11 CreERT2 developed cardiac hypertrophy with decreased ejection fraction (65 vs 58, SEM= 2, n=7, p<0.001) and increased systolic (1.33 mm vs 1.8 mm, SEM= 0.1, n=7, p<0.01) and diastolic LVD (1.33 mm vs 1.52 mm, SEM= 0.08, n=7, p< 0.01). Cardiomyocyte area was increased in the Myh11 CreERT2 mice compared to the Sox6KO animals (area - square microns, 300 vs 100, SEM= 36, n=3, p<.001). The Sox6KO mice had a higher base line LVD in both diastole and systole. However, the cardiomyocytes area was similar to normotensive Myh11 CreERT2 mice. Conclusion: Hypertension in control Myh11 CreERT2 animals was associated with impaired cardiac function. In contrast, there was no decrease in cardiac function in hypertensive Sox6KO mice. While in Myh11 CreERT2 mice, Ang II induced significant cardiomyocyte hypertrophy, in Sox6KO mice, Ang II did not induce cardiomyocytes hypertrophy. These results suggest that Sox6 signaling in SMCs is a critical mediator of hypertension induced cardiomyocyte hypertrophy.