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Published on: September 18, 2017
Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling
Saumya Das1, Takeshi Aiba, Michael Rosenberg
1Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Insights
Serum- and glucocorticoid-regulated kinase-1 (SGK1) is activated in heart failure, worsening cardiac dysfunction and arrhythmias. Inhibiting SGK1 protects the heart, suggesting it as a therapeutic target for cardiac disease.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Biomedical Research
Background:
- Heart failure is a significant cause of mortality and morbidity.
- Cardiac phosphatidylinositol 3-kinase (PI3K) signaling is paradoxically activated in heart failure.
- The downstream effector serum- and glucocorticoid-regulated kinase-1 (SGK1) was investigated in heart failure.
Purpose of the Study:
- To investigate the role of SGK1 in the pathogenesis of heart failure.
- To determine if SGK1 is a potential therapeutic target for cardiac disease.
Main Methods:
- Utilized cardiac-specific expression of constitutively active or dominant-negative SGK1 in murine models.
- Assessed mortality, cardiac function, ventricular arrhythmias, and cardiac sodium channel function.
- Investigated the effects of ranolazine on SGK1-induced proarrhythmic effects.
- Evaluated the impact of SGK1 inhibition on cardiac fibrosis and heart failure after hemodynamic stress.
Main Results:
- Cardiac SGK1 was found to be activated in human and murine heart failure.
- Cardiac-specific activation of SGK1 in mice led to increased mortality, cardiac dysfunction, and ventricular arrhythmias.
- SGK1-induced arrhythmias were linked to alterations in the cardiac sodium channel and were reversed by ranolazine.
- Cardiac-specific inhibition of SGK1 protected mice from fibrosis, heart failure, and sodium channel alterations following hemodynamic stress.
Conclusions:
- SGK1 is both necessary and sufficient for key features of adverse ventricular remodeling in heart failure.
- SGK1 represents a potential novel therapeutic target for cardiac disease.
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.
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