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Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
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.
Circulation
|September 29, 2012
Summary
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.
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