Pathological Role of Serum- and Glucocorticoid-Regulated Kinase 1 in Adverse Ventricular Remodeling

• DOI: 10.1161/circulationaha.112.115592
• Publication Date: 2012-09-27T15:19:10Z
• Authors: Saumya Das; Takeshi Aiba; Michael Rosenberg; Katherine Hessler; Chunyang Xiao; Pablo A. Quintero; Filomena G. Ottav...; Ashley C. Knight; Evan L. Graham; Pontus Boström; Michael R. Moriss...; Federica del Monte; Michael J. Begley; Lewis C. Cantley; Patrick T. Ellinor; Gordon F. Tomaselli; Anthony Rosenzweig
• Keywords: Ventricular remodeling

Background— Heart failure is a growing cause of morbidity and mortality. Cardiac phosphatidylinositol 3-kinase signaling promotes cardiomyocyte survival function, but it paradoxically activated in heart failure, suggesting that chronic activation this pathway may become maladaptive. Here, we investigated the downstream effector, serum- glucocorticoid-regulated kinase-1 (SGK1), its complications. Methods Results— We found cardiac SGK1 human murine failure. role by using cardiac-specific expression constitutively active or dominant-negative SGK1. Cardiac-specific mice increased mortality, dysfunction, ventricular arrhythmias. The proarrhythmic effects were linked to biochemical functional changes sodium channel could be reversed treatment with ranolazine, blocker late current. Conversely, inhibition protected after hemodynamic stress from fibrosis, alterations. Conclusions— appears both necessary sufficient for key features adverse remodeling provide novel therapeutic target disease.