Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, plays an important role in regulating growth and death of cardiomyocytes. During the current funding cycle, we established that GSK-3 is a negative regulator of cardiac hypertrophy and has substantial influence on cardiac function when its activity is modulated by phosphorylation during hypertrophy and heart failure (HF). Furthermore, our recent study conducted using GSK-3a(S21A) and GSK-3b(S9A) knock-in (KI) mice demonstrated that GSK-3 has isoform specific functions, which may be attributed to the distinct subcellular localizations of GSK-3a and GSK-3b. Unexpectedly, S21 phosphorylation of GSK-3a and S9 phosphorylation GSK-3b exhibited opposite functional consequences in the heart under pressure overload, indicating the importance of re-evaluating the function of the GSK-3 isoforms with special emphasis on their subcellular localization and unique targets. Thus, one important theme in this proposal is to demonstrate that endogenous GSK-3a and GSK-3b, localized in different subcellular locations/compartments, play distinct roles in mediating growth, death and differentiation of cardiomyocytes and their precursor cells. In particular, we will elucidate the isoform-specific functions of GSK-3 during pressure overload-induced cardiac hypertrophy, ischemia/reperfusion (I/R) and differentiation of bone marrow (BM)-derived mesenchymal stem cells (MSCs) by focusing on novel connections between GSK-3 isoforms and their downstream targets. Our hypotheses are: 1. GSK-3a, primarily localized in the nucleus, regulates expression of E2F in adult hearts. Phosphorylation of GSK-3a and subsequent upregulation of E2F is a compensatory mechanism to supplement myocyte proliferation and prevent mitochondrial dysfunction during pressure overload. 2. GSK-3b regulates survival and death of cardiomyocytes during I/R. Activation of GSK-3b during ischemia inhibits mTOR through a TSC2-dependent mechanism, stimulates autophagy, and protects the heart from cell death. On the other hand, phosphorylation/inactivation of GSK-3b during reperfusion is beneficial through activation of mTOR. 3. Upregulation of GSK-3b and downregulation of GSK- 3a facilitate differentiation of BM-derived MSCs into the cardiomyocyte lineage through distinct molecular mechanisms. Injection of MSCs in which GSK-3b is upregulated and GSK-3a is downregulated ex vivo facilitates the recovery of the heart after myocardial infarction (MI) through stimulation of cardiomyocyte differentiation and angiogenesis. We will address these issues, using genetically altered mouse models and integrated molecular and physiological approaches. Our study will elucidate the isoform-specific functions and unique downstream targets of GSK-3a and GSK-3b in mediating both growth/death and differentiation in the heart under stresses. The knowledge obtained from this investigation will lead to a better understanding of the molecular mechanisms mediating HF, ischemic injury, and stem cell differentiation, which can be utilized to develop specific interventions to treat HF and ischemic heart disease, and improve cell-based therapies.

Public Health Relevance

Despite recent progress in medical therapy, heart failure is one of the most common causes of death in western countries. Understanding the molecular mechanism mediating growth and death of cardiac muscle is fundamentally important and potentially leads to better medical treatment for heart failure. This laboratory has been working on an enzyme termed glycogen synthase kinase-3, which plays an essential role in regulating growth and death of cardiomyocytes. Although this enzyme in the heart exists as two distinct forms, namely alpha and beta isoforms, the function of each form is not well understood. We will investigate the function of each isoform during heart failure, ischemic heart disease and stem cell differentiation, using genetically modified mice and mouse models of heart failure and ischemia/reperfusion injury. The knowledge obtained from this investigation should be useful for the development of better treatment for heart failure, ischemic injury and stem cell therapy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Buxton, Denis B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Medicine & Dentistry of NJ
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Maejima, Yasuhiro; Chen, Yun; Isobe, Mitsuaki et al. (2015) Recent progress in research on molecular mechanisms of autophagy in the heart. Am J Physiol Heart Circ Physiol 308:H259-68
Yamamoto, Takanobu; Byun, Jaemin; Zhai, Peiyong et al. (2014) Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. PLoS One 9:e98972
Maejima, Yasuhiro; Sadoshima, Junichi (2014) SUMOylation: a novel protein quality control modifier in the heart. Circ Res 115:686-9
Maejima, Yasuhiro; Usui, Soichiro; Zhai, Peiyong et al. (2014) Muscle-specific RING finger 1 negatively regulates pathological cardiac hypertrophy through downregulation of calcineurin A. Circ Heart Fail 7:479-90
Sciarretta, Sebastiano; Yee, Derek; Shenoy, Varun et al. (2014) The importance of autophagy in cardioprotection. High Blood Press Cardiovasc Prev 21:21-8
Sciarretta, Sebastiano; Volpe, Massimo; Sadoshima, Junichi (2014) Mammalian target of rapamycin signaling in cardiac physiology and disease. Circ Res 114:549-64
Del Re, Dominic P; Matsuda, Takahisa; Zhai, Peiyong et al. (2014) Mst1 promotes cardiac myocyte apoptosis through phosphorylation and inhibition of Bcl-xL. Mol Cell 54:639-50
Shao, Dan; Oka, Shin-Ichi; Liu, Tong et al. (2014) A redox-dependent mechanism for regulation of AMPK activation by Thioredoxin1 during energy starvation. Cell Metab 19:232-45
Yu, Qiujun; Lee, Chi Fung; Wang, Wang et al. (2014) Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury. J Am Heart Assoc 3:e000555
Hsu, Chiao-Po; Yamamoto, Takanobu; Oka, Shinichi et al. (2014) The function of nicotinamide phosphoribosyltransferase in the heart. DNA Repair (Amst) 23:64-8

Showing the most recent 10 out of 106 publications