Remodeling of the left ventricle (LV), which includes dilatation, reduced contractile function, and, typically, increased fibrosis, is a major problem following myocardial infarction (MI) or severe pressure stress as one sees in advanced hypertension or valvular disease. Remodeling typically culminates in heart failure. Current therapeutics are inadequate, and while they can slow the progression of remodeling, the remodeling does inexorably progress. It is very clear that prevention of remodeling is an unmet need in cardiovascular disease. We have recently employed novel mouse models to identify critical roles for the GSK-3 family of protein kinases in remodeling post-MI and post-thoracic aortic constriction (TAC). In brief, deletion of the gene encoding GSK-3b is protective in the post-MI state. In stark contrast, deletion of the gene encoding GSK-3a leads to profound heart failure following either MI or TAC, due at least in part to markedly impaired b-adrenergic responsiveness. It is the purpose of this competing renewal application to extend our studies examining the role of the GSK-3 family in pathologic disease states in the heart. We plan to examine a very poorly understood issue: the role of the GSK-3 family in post-injury fibrosis, utilizing mouse models in which GSK-3a vs. GSK-3b is selectively knocked out in cardiomyocytes vs. fibroblasts. Our preliminary studies suggest that GSK-3a functions as a critical break on fibrosis. We will also identify the molecular mechanism by which GSK-3a regulates b-adrenergic responsiveness. The latter studies could lead to alternative strategies to traditional b-blockade, with the additional advantage that deletion (or inhibition) of GSK- 3a, unlike b-blockers, leads to improved glucose tolerance and insulin sensitivity.

Public Health Relevance

Is this competing renewal we propose to extend our studies on the many roles played by GSK-3 family members in pathologic processes in the heart. Specifically, we will examine remodeling in the post-MI and post aortic-banded heart. We will also examine the role played by GSK-3 in regulating post-injury fibrosis, utilizing mice deleted for GSK-3a vs. -3b, in cardiomyocytes vs. fibroblasts. Finally, we have found that GSK-3a positively regulates the b1-adrenergic system, and in the absence of GSK-3a, the stressed heart rapidly fails. In Aim 3 we will identify the molecular mechanism by which GSK-3a regulates this critically important system.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Temple University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Lal, Hind; Ahmad, Firdos; Parikh, Shan et al. (2014) Troponin I-interacting protein kinase: a novel cardiac-specific kinase, emerging as a molecular target for the treatment of cardiac disease. Circ J 78:1514-9
Lal, Hind; Ahmad, Firdos; Zhou, Jibin et al. (2014) Cardiac fibroblast glycogen synthase kinase-3? regulates ventricular remodeling and dysfunction in ischemic heart. Circulation 130:419-30
Ahmad, Firdos; Lal, Hind; Zhou, Jibin et al. (2014) Cardiomyocyte-specific deletion of Gsk3? mitigates post-myocardial infarction remodeling, contractile dysfunction, and heart failure. J Am Coll Cardiol 64:696-706
Lal, Hind; Kolaja, Kyle L; Force, Thomas (2013) Cancer genetics and the cardiotoxicity of the therapeutics. J Am Coll Cardiol 61:267-74
Force, Thomas; Wang, Yibin (2013) Mechanism-based engineering against anthracycline cardiotoxicity. Circulation 128:98-100
Ky, Bonnie; Vejpongsa, Pimprapa; Yeh, Edward T H et al. (2013) Emerging paradigms in cardiomyopathies associated with cancer therapies. Circ Res 113:754-64
Cheng, Hui; Woodgett, James; Maamari, Mia et al. (2011) Targeting GSK-3 family members in the heart: a very sharp double-edged sword. J Mol Cell Cardiol 51:607-13
Hernandez, Gonzalo; Lal, Hind; Fidalgo, Miguel et al. (2011) A novel cardioprotective p38-MAPK/mTOR pathway. Exp Cell Res 317:2938-49
Cheng, Hui; Kari, Gabor; Dicker, Adam P et al. (2011) A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity. Circ Res 109:1401-9
Kerkelä, Risto; Boucher, Matthieu; Zaka, Raihana et al. (2011) Cytosolic phospholipase A(2)? protects against ischemia/reperfusion injury in the heart. Clin Transl Sci 4:236-42

Showing the most recent 10 out of 36 publications