Alterations in Ca2+ cycling proteins and Gαq signaling after left ventricular assist device support in failing human hearts

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Abstract
Objective: Left ventricular assist device support mechanically unloads the failing ventricle with resultant improvement in cardiac geometry and function in patients with end-stage heart failure. Activation of the Gαq signaling pathway, including protein kinase C, appears to be involved in the progression of heart failure. Similarly down-regulation of Ca2+ cycling proteins may contribute to contractile depression in this clinical syndrome. Thus we examined whether protein kinase C activation and decreased Ca2+ cycling protein levels could be reversed by left ventricular assist device support. Methods: Left ventricular myocardial specimens were obtained from seven patients during placement of left ventricular assist device and heart transplantation. We examined changes in protein levels of Gαq, phospholipase C β1, regulators of G protein signaling (RGS), sarcoplasmic reticulum Ca2+ ATPase, phospholamban and translocation of protein kinase C isoforms (α, β1, and β2). Results: The paired pre- and post- left ventricular assist device samples revealed that RGS2, a selective inhibitor of Gαq, was decreased ( P <0.01), while the status of Gαq, phospholipase C β1, RGS3 and RGS4 were unchanged after left ventricular assist device implantation. Translocation of protein kinase C isoforms remained unchanged. Left ventricular assist device support increased sarcoplasmic reticulum Ca2+ ATPase protein level ( P <0.01), while phospholamban abundance was unchanged. Conclusions: We conclude that altered protein expression and stoichiometry of the major cardiomyocyte Ca2+ cycling proteins rather than reduced phospholipase C β1 activation may contribute to improved mechanical function produced by left ventricular assist device support in human heart failure.

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