Abstract 309: Two SoxD Family Transcription Factors Influence Heart Function at Baseline and After Cardiac Overload

Abstract

Background: Sox6, a member of the SoxD family of transcription factors, has recently been established as a mediator of the actions of MyomiRs miR-208b and 499 in skeletal muscle. Sox6 suppresses the expression of slow skeletal muscle genes and its deletion promotes skeletal muscle fiber switching in mice. However, the role of Sox6 in the heart remains elusive. Given the importance of MyomiRs in regulating cardiac stress responses and the regulation of Sox6 by MyomiRs in the heart, we postulate that Sox6 is a central regulator of cardiac hypertrophy and heart failure. Results: Because of functional redundancy of Sox6 and Sox5 in multiple tissues, Sox6 fl/fl mice were crossbred with Sox5 fl/fl mice and mice expressing CRE recombinase under the control of the alphaMHC gene promoter to obtain Sox5 fl/fl / Sox6 fl/fl /CRE+ ( Sox5/6 cKO) animals or CRE- controls. Sox5/6 cKO animals were viable and born at expected Mendelian ratios. At baseline, Sox5/6 cKO mice did not show any signs of hypertrophy or cardiac failure as assessed by echocardiography at the age of 9 weeks. While cardiac size and heart function measured by echocardiography was unaltered in mice aged 4-5 months, cardiac catheterization revealed significant decreases in contractility in Sox5/6 cKO animals. In addition, qPCR analysis of hearts showed increased expression of slow myosin Myh7 and Nppa , a marker of cardiac stress, in Sox5/6 cKO animals compared to controls. Following cardiac pressure overload for 3 weeks by transverse aortic constriction (TAC), significant decreases in cardiac function, as measured by echocardiography, were apparent in Sox5/6 cKO compared to control mice. Sox5/6 cKO mice subjected to TAC also showed signs of cardiac failure such as increased wet lung weight. Conclusion: Cardiac-specific deletion of Sox6 and Sox5 lead to reduction of cardiac function at baseline and exacerbated susceptibility to the development of cardiac failure after cardiac pressure overload. The contribution of each individual transcription factor to the observed phenotypes is currently being investigated.