title: Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling.
abstract: BACKGROUND
  Heart failure is a growing cause of morbidity and mortality. Cardiac phosphatidylinositol 3-kinase signaling promotes cardiomyocyte survival and function, but it is paradoxically activated in heart failure, suggesting that chronic activation of this pathway may become maladaptive. Here, we investigated the downstream phosphatidylinositol 3-kinase effector, serum- and glucocorticoid-regulated kinase-1 (SGK1), in heart failure and its complications.
  
  
  RESULTS
  We found that cardiac SGK1 is activated in human and murine heart failure. We investigated the role of SGK1 in the heart by using cardiac-specific expression of constitutively active or dominant-negative SGK1. Cardiac-specific activation of SGK1 in mice increased mortality, cardiac dysfunction, and ventricular arrhythmias. The proarrhythmic effects of SGK1 were linked to biochemical and functional changes in the cardiac sodium channel and could be reversed by treatment with ranolazine, a blocker of the late sodium current. Conversely, cardiac-specific inhibition of SGK1 protected mice after hemodynamic stress from fibrosis, heart failure, and sodium channel alterations.
  
  
  CONCLUSIONS
  SGK1 appears both necessary and sufficient for key features of adverse ventricular remodeling and may provide a novel therapeutic target in cardiac disease.
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Saumya
authors.initials: S
authors.lastname: Das
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aiba
authors.forename: Michael
authors.initials: M
authors.lastname: Rosenberg
authors.forename: Katherine
authors.initials: K
authors.lastname: Hessler
authors.forename: Chunyang
authors.initials: C
authors.lastname: Xiao
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Quintero
authors.forename: Filomena G
authors.initials: FG
authors.lastname: Ottaviano
authors.forename: Ashley C
authors.initials: AC
authors.lastname: Knight
authors.forename: Evan L
authors.initials: EL
authors.lastname: Graham
authors.forename: Pontus
authors.initials: P
authors.lastname: Boström
authors.forename: Michael R
authors.initials: MR
authors.lastname: Morissette
authors.forename: Federica
authors.initials: F
authors.lastname: del Monte
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Begley
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Tomaselli
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
mesh_terms: D000083:Acetanilides / Q000627:therapeutic use; D000818:Animals; D059267:Cardiomegaly, Exercise-Induced; D002311:Cardiomyopathy, Dilated / Q000201:enzymology*; D016384:Consensus Sequence; D004195:Disease Models, Animal; D004562:Electrocardiography; D004790:Enzyme Induction; D006333:Heart Failure / Q000201:enzymology*; D006801:Humans; D006973:Hypertension / Q000150:complications; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000069458:Ranolazine; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D017180:Tachycardia, Ventricular / Q000201:enzymology / Q000209:etiology; D020257:Ventricular Remodeling / Q000502:physiology*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000083:Acetanilides; D017874:Immediate-Early Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D000069458:Ranolazine; D026941:Sodium Channel Blockers; D000099184:Serum-Glucocorticoid Regulated Kinases; C568321:Scn5a protein, mouse