Adverse cardiac remodeling is a common prelude to heart failure and arrhythmia, but little is known about the signaling mechanisms that mediate this transition. Serum- and glucocorticoid-regulated kinase-1 (SGK1) is a PI3-kinase (PI3K)-dependent kinase that is activated in pathological hypertrophy and heart failure (HF) but not in physiological hypertrophy. SGK1 shares some downstream substrates (e.g. GSK3 and Foxo3) with other PI3K-dependent kinases, such as Akt1, but also has unique downstream effects including modulation of ion channels such as potassium channels and the cardiac sodium channel, SCN5a. While we have previously shown that SGK1 regulates cardiomyocyte (CM) survival and growth in vitro, its role in CM in vivo and the effects of chronic SGK1 activation or inhibition are largely unknown. To address these questions in vivo, we generated cardiac-specific transgenic (TG) mice expressing either a constitutively active (CA) or dominant negative (DN) form of the SGK1 kinase. While SGK1-CA TG mice exhibit spontaneous and inducible arrhythmias, SGK1-DN TG mice appear normal at baseline. In a model of cardiac hypertrophy and heart failure induced by transverse aortic constriction (TAC), SGK1-DN TGs are substantially protected against cardiac dysfunction and fibrosis. SGK1 activation led to significant alterations in post-translational modification and subcellular distribution of SCN5a protein. This was associated with altered channel kinetics and gating, as well as an increase in late sodium current (INaL) and action potential duration (APD). The major goal of this proposal is to understand the role of SGK1 in electrical remodeling in the context of pathological hypertrophy and HF. This proposal is based on four hypotheses: 1) that chronic activation of SGK1 in CMs is an important mediator of adverse electrical remodeling in HF, 2) that inhibition of SGK1 in CMs will mitigate adverse remodeling, 3) that altered SCN5a function and INaL are important contributors to these effects, and 4) that other novel SGK1 substrates also play a role in the observed phenotypes. To test these hypotheses, we will utilize mice with CM-specific expression of SGK1-CA or -DN at baseline and in models of hypertrophy and/or HF.
In Aim 1, we will examine the effects of activating or inhibiting SGK1 on electrical remodeling at baseline and after aortic banding.
In Aim 2, we will define the cellular mechanisms responsible for the observed electrophysiological phenotypes. Finally, in Aim 3, we will delineate the molecular mechanisms mediating these phenotypes through focused interrogation of known downstream pathways, and subtractive screens for novel effectors. Arrhythmia remains an important cause of morbidity and mortality in HF. Understanding the role of SGK1 in adverse electrical remodeling and arrhythmic complications of HF could yield novel therapeutic approaches for this important condition.

Public Health Relevance

Patients with heart failure or thickened (hypertrophied) heart muscle are at increased risk for heart rhythm problems, some of which can be fatal. Our goal is to understand the role of a specific molecule (SGK1) in the development of heart rhythm problems in this context. We will study this question in mice in which we have genetically activated or inhibited this molecule specifically in heart muscle cells. Our initial results suggest that activating this molecule promotes rhythm problems, whereas inhibiting it has beneficial effects. While we think it is important in general to understand mechanisms underlying heart rhythm problems, this molecule is particularly interesting because it belongs to a class of molecules that have previously been successfully targeted for drug development. Thus understanding SGK1's role in the heart could have important practical implications, and the current application would help advance our understanding of the potential of SGK1 as a therapeutic target.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Schwartz, Lisa
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Beth Israel Deaconess Medical Center
United States
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Simonson, Bridget; Subramanya, Vinita; Chan, Mun Chun et al. (2017) DDiT4L promotes autophagy and inhibits pathological cardiac hypertrophy in response to stress. Sci Signal 10:
Dai, Jing; Matsui, Takashi; Abel, E Dale et al. (2014) Deep sequence analysis of gene expression identifies osteopontin as a downstream effector of integrin-linked kinase (ILK) in cardiac-specific ILK knockout mice. Circ Heart Fail 7:184-93
Vernochet, Cecile; Damilano, Federico; Mourier, Arnaud et al. (2014) Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications. FASEB J 28:4408-19
Das, Saumya; Aiba, Takeshi; Rosenberg, Michael et al. (2012) Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling. Circulation 126:2208-19
Aoyagi, Toshinori; Kusakari, Yoichiro; Xiao, Chun-Yang et al. (2012) Cardiac mTOR protects the heart against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 303:H75-85
Bezzerides, Vassilios; Rosenzweig, Anthony (2011) Saying yes to exercise and NO to cardiac injury. Circ Res 108:1414-6
Kusakari, Yoichiro; Xiao, Chun-Yang; Himes, Nathan et al. (2009) Myocyte injury along myofibers in left ventricular remodeling after myocardial infarction. Interact Cardiovasc Thorac Surg 9:951-5