Abstract
Heart failure is one of the major causes of death worldwide. Its pathophysiology is complex and involves alterations in calcium cycling and hypertrophic signaling, as well as subsequent loss of cardiomyocytes due to apoptosis, cardiac fibrosis and progressive contractile dysfunction. The Striatin-interacting phosphatase and kinase (STRIPAK) complex is a mammalian multiprotein complex that consists of phosphatases, kinases and various adaptor proteins. Yet, the STRIPAK complex has so far not been studied in cardiomyocytes. Now we show in cardiomyocytes that the STRIPAK associated kinase MST4 directly interacts with a recently described novel cardiac STRIPAK protein, Myoscape/STRIP2. Multi tissue immunoblot experiments showed that Mst4 abundance is also highly enriched in heart and skeletal muscle. Immunoblot analyses in human biopsy samples form patients with dilated (DCM n=10) or ischemic cardiomyopathy (ICM n=10) revealed that MST4 is strongly upregulated in DCM (12-fold p<0.001) and ICM (9.6 fold p<0.05) vs. controls. Conversely, upon biomechanical stretch we observed a significant downregulation of MST4 in vitro by 30% (p<0.05) as well as in vivo (-45%, n=6; P<0.001) in a murine model for pressure overload (experimental aortic constriction, (TAC) vs. Sham) under Moreover, we also observed downregulation of MST4 in a porcine myocardial infarction model (-48% vs. porcine controls; n=5 p<0.05). Adenoviral overexpression of MST4 in NRVCM results in significant cellular hypertrophy (485μm2 vs 421μm2; p<0.001) compared to LacZ. Overexpression of MST4 also increases cellular and sarcomeric fractional shortening in adult rat cardiac myocytes vs. LacZ (p<0.05). Finally, MST4 overexpression also protects from cardiac apoptosis as shown by 90% reduced PARP cleavage as well as significantly reduced expression of Caspase 3 and 7 (n=3; p<0.05). Taken together we show that MST 4 is a cardiac enriched Kinase that regulates cardiomyocyte hypertrophy, contractility and apoptosis and may thus be a target for future therapeutic intervention
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