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

Saumya Das, Takeshi Aiba, Michael Rosenberg, Katherine Hessler, Chunyang Xiao, Pablo A. Quintero, Filomena G. Ottaviano, Ashley C. Knight, Evan L. Graham, Pontus Boström, Michael R. Morissette, Federica Del Monte, Michael J. Begley, Lewis C. Cantley, Patrick T. Ellinor, Gordon F. Tomaselli, Anthony Rosenzweig

Research output: Contribution to journalArticle

46 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)2208-2219
Number of pages12
JournalCirculation
Volume126
Issue number18
DOIs
StatePublished - Oct 30 2012
Externally publishedYes

Fingerprint

Ventricular Remodeling
Heart Failure
Phosphatidylinositol 3-Kinase
Sodium Channels
Ventricular Dysfunction
Mortality
serum-glucocorticoid regulated kinase
Cardiac Myocytes
Cardiac Arrhythmias
Heart Diseases
Fibrosis
Hemodynamics
Sodium
Morbidity

Keywords

  • arrhythmia
  • heart failure
  • ion channels or ion channel
  • signal transduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Das, S., Aiba, T., Rosenberg, M., Hessler, K., Xiao, C., Quintero, P. A., ... Rosenzweig, A. (2012). Pathological role of serum-and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling. Circulation, 126(18), 2208-2219. https://doi.org/10.1161/CIRCULATIONAHA.112.115592

Pathological role of serum-and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling. / Das, Saumya; Aiba, Takeshi; Rosenberg, Michael; Hessler, Katherine; Xiao, Chunyang; Quintero, Pablo A.; Ottaviano, Filomena G.; Knight, Ashley C.; Graham, Evan L.; Boström, Pontus; Morissette, Michael R.; Del Monte, Federica; Begley, Michael J.; Cantley, Lewis C.; Ellinor, Patrick T.; Tomaselli, Gordon F.; Rosenzweig, Anthony.

In: Circulation, Vol. 126, No. 18, 30.10.2012, p. 2208-2219.

Research output: Contribution to journalArticle

Das, S, Aiba, T, Rosenberg, M, Hessler, K, Xiao, C, Quintero, PA, Ottaviano, FG, Knight, AC, Graham, EL, Boström, P, Morissette, MR, Del Monte, F, Begley, MJ, Cantley, LC, Ellinor, PT, Tomaselli, GF & Rosenzweig, A 2012, 'Pathological role of serum-and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling', Circulation, vol. 126, no. 18, pp. 2208-2219. https://doi.org/10.1161/CIRCULATIONAHA.112.115592
Das, Saumya ; Aiba, Takeshi ; Rosenberg, Michael ; Hessler, Katherine ; Xiao, Chunyang ; Quintero, Pablo A. ; Ottaviano, Filomena G. ; Knight, Ashley C. ; Graham, Evan L. ; Boström, Pontus ; Morissette, Michael R. ; Del Monte, Federica ; Begley, Michael J. ; Cantley, Lewis C. ; Ellinor, Patrick T. ; Tomaselli, Gordon F. ; Rosenzweig, Anthony. / Pathological role of serum-and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling. In: Circulation. 2012 ; Vol. 126, No. 18. pp. 2208-2219.
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