Septin4 Induces Fibrosis After Cardiac Pressure Overload Injury
2023-02
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Septin4 Induces Fibrosis After Cardiac Pressure Overload Injury
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2023-02
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In response to cardiac injury the mammalian heart undergoes ventricular remodeling to maintain cardiac function. These changes are initially considered compensatory, but eventually lead to increased cardiomyocyte apoptosis, reduced cardiac function and fibrosis which are important contributors to the development of HF. The small GTPase Septin4 (Sept4) has previously been implicated in the regulation of regeneration and apoptosis in several organs. A role for Sept4 in regulating the response to cardiac stress is unknown. To investigate the role of Sept4 in cardiac stress response, we performed were subjected to transverse aortic constriction on 10-week-old wild type (WT) and Sept4 knockout (KO) mice. Under homeostatic conditions Sept4 KO mice showed normal cardiac function comparable with WT controls. In response to TAC, WT mice developed reduced cardiac function and HF, accompanied by an increase in cardiomyocyte apoptosis. In contrast, KO mice were protected against injury with maintenance of normal cardiac function and reduced levels of cardiomyocyte apoptosis. Both at baseline and after TAC injury, KO hearts exhibited decreased levels of cardiac ECM deposition and fibrosis compared with WT controls. In support of these data, the level of myofibroblast activation was lower after injury in KO mice. Furthermore, KO mice showed higher levels of cardiac elasticity and improved diastolic function compared with WT controls. Mechanistically, we identified reduced expression of cross- linking collagens at both RNA and protein levels. Molecularly, Sept4 deletion blunted TGF-β signaling and reduced Postn expression. Based on our results, we identified Sept4 as an important regulator of ECM remodeling in the heart. We speculate that the changes in ECM composition observed in KO hearts help alleviate the cardiac pathology resulting from cardiac pressure overload.
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University of Minnesota Ph.D. dissertation. February 2023. Major: Integrative Biology and Physiology. Advisor: Jop van Berlo. 1 computer file (PDF); iii, 142 pages.
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Yucel, Dogacan. (2023). Septin4 Induces Fibrosis After Cardiac Pressure Overload Injury. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/262003.
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