Abstract 17626: Myoscape, a Novel Member of the Stripak Complex, Controls Contractile Function and Hypertrophy in vitro and in vivo via Modulation of Calcineurin Nfat Activity and its Interaction With Pp2a
Alterations in cardiomyocyte calcium cycling have been shown to play a major role in the pathophysiology of contractile dysfunction, cardiomyocyte hypertrophy and heart failure. The mammalian Striatin-interacting phosphatase and kinase (STRIPAK) complex consist of many proteins, among them phosphatase PP2A and Myoscape/ STRIP2. A role of STRIPAK in the heart has not been described. We recently showed that Myoscape/STRIP2 directly interacts with the distal C-terminus of the L-type Ca2+channel and cardiac Alpha-Actinin 2 to stabilize LTCC surface expression. Now we show that Myoscape also directly interacts and co-localizes with PP2A in cardiomyocytes. PP2A is thought to dephosphorylate LTCC at Ser1928 thereby antagonizing catecholaminergic PKA activity. In vitro adenoviral knockdown of Myoscape in NRVCM results in increased cell size (460μm2 vs 680μm2; p<0,001) and increased levels of ANF and BNP. Beyond that Myoscape depleted NRVCM showed increased basal Calcineurin NFAT luciferase activity as compared to controls. Calcineurin signalling was further enhanced after treatment of Myoscape depleted NRVCM with PE (100μM). In contrast, overexpression of Myoscape was able to suppress Calcineurin NFAT luciferase in NRVCM, resulting in decreased levels of ANF and BNP (51% vs control and 48% vs control respectively; p<0,05; n=3). Moreover, adenoviral overexpression of Myoscape partially reversed cardiomyocyte hypertrophy after PE treatment in vitro (420μm Adlacz; 880μm Adlacz+PE vs. 630μm AdMyoscape+PE; n=3 p<0.05). After 4 weeks of aortic constriction Myoscape null mice showed significantly deteriorated contractile function with progressive ventricular dilatation, enhanced fibrosis and increased pulmonary blood congestion as compared to wildtype littermates. Myoscape KO’s showed increased heart weight to tibia length ratios and developed significantly exaggerated cardiomyocyte hypertrophy. This was also accompanied by a significant RCAN1.4 induction in TAC KO mice compared to TAC WT, indicating strong Calcineurin activity accompanied by super induction of ANF and BNP. In line with these results TAC KO mice showed a significant decrease in LTCC phosphorylation at residue SER1928, indicating increased uncoupled PP2A activity.
Author Disclosures: M. Eden: None. P. Doldi: None. C. Tannert: None. M. Branchereau: None. P. Marck: None. C. Heymes: None. F. Norbert: None.
- © 2016 by American Heart Association, Inc.