Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling

Autor: Saumya Das, Gordon F. Tomaselli, Michael A. Rosenberg, Filomena G. Ottaviano, Katherine Hessler, Patrick T. Ellinor, Michael J. Begley, Ashley C. Knight, Anthony Rosenzweig, Federica del Monte, Takeshi Aiba, Chunyang Xiao, Pablo A. Quintero, Pontus Boström, Lewis C. Cantley, Evan L. Graham, Michael R. Morissette
Rok vydání: 2012
Předmět:
Cardiomyopathy
Dilated
medicine.medical_specialty
Cardiomyopathy
Ranolazine
Mice
Transgenic
Protein Serine-Threonine Kinases
Immediate early protein
Piperazines
Immediate-Early Proteins
NAV1.5 Voltage-Gated Sodium Channel
chemistry.chemical_compound
Electrocardiography
Mice
Phosphatidylinositol 3-Kinases
Sodium channel blocker
Physiology (medical)
Internal medicine
Consensus Sequence
Protein Interaction Mapping
medicine
Animals
Humans
Phosphatidylinositol
Cardiomegaly
Exercise-Induced
Phosphorylation
Ventricular remodeling
Heart Failure
Ventricular Remodeling
urogenital system
business.industry
medicine.disease
Mice
Inbred C57BL
Disease Models
Animal
Endocrinology
chemistry
Heart failure
Enzyme Induction
Hypertension
SGK1
Tachycardia
Ventricular
Acetanilides
Cardiology and Cardiovascular Medicine
business
Ion Channel Gating
Protein Processing
Post-Translational
medicine.drug
Sodium Channel Blockers
Zdroj: Circulation. 126(18)
ISSN: 1524-4539
Popis: 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. Methods and 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.
Databáze: OpenAIRE
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