Cardiac hypertrophy and heart failure are leading causes of death in the United States. However, the molecular processes underlying the pathogenesis of heart disease have not been thoroughly understood. During investigations spanning several years we identified and profiled in spontaneously hypertensive rats a 12-kDa protein, myotrophin (Myo), that stimulates myocyte growth. The past funding period has yielded these novel observations: (1) Myo overexpression causes cardiac hypertrophy that devolves to heart failure, and the molecular profiles of associated cytokines/growth factors differ in early- vs. late-stage disease; (2) activation of the NFkappaB pathway is necessary for the progression of Myo-induced cardiac hypertrophy; (3) at the point when chronic hypertrophy becomes heart failure, cell division and apoptosis of cardiac myocytes occur in parallel; and (4) Myo overexpression elicits significant, robust overexpression of p53, highlighting a possible role of p53 in this process. Each finding would provide fertile ground for more investigation, but we chose in this renewal proposal to focus on the effects of turning Myo gene expression on and off and defining the role of p53 in the hypertrophic process. We hypothesize that Myo acts directly on myocyte during initiation of cardiac hypertrophy, whereas it acts in synergy with p53 and other cytokines/growth factors at the point of transition to heart failure. To test this hypothesis, we propose a multidisciplinary approach to evaluating the effects of the expression or nonexpression of the Myo gene by (a) using a let-control switch; (b) silencing the Myo gene using siRNA technology; or (c) administering pharmacological treatment conventionally given to humans with heart failure.
Our specific aims are (1) to study the effects of altering Myo gene expression by either (a) using a tetracycline transactivation system or (b) silencing the Myo gene using siRNA; (2) to study the effects of individual pharmacologic agents, alone or in combination, on the degree of hypertrophy as it progresses to heart failure, associated with molecular changes; (3) to define what relationship p53 has to Myo in hypertrophy and when it worsens to failure; (4) to evaluate structural changes observed during initiation/progression of hypertrophy to heart failure by transmission electron microscopy and (5) to determine cardiac function by echocardiogram to correlate observed morphological and molecular changes. These findings bear crucially upon the treatment of heart disease in humans. Together with investigations into additional molecular mechanisms that underlie the progression of cardiac hypertrophy to heart failure, the findings will facilitate more effective intervention, not only in decisions regarding the timing of intervention, but also in the design of appropriate molecularly based therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Liang, Isabella Y
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Vasudevan, Neelakantan T; Mohan, Maradumane L; Gupta, Manveen K et al. (2013) G??-independent recruitment of G-protein coupled receptor kinase 2 drives tumor necrosis factor ?-induced cardiac ?-adrenergic receptor dysfunction. Circulation 128:377-87
Das, Biswajit; Young, David; Vasanji, Amit et al. (2010) Influence of p53 in the transition of myotrophin-induced cardiac hypertrophy to heart failure. Cardiovasc Res 87:524-34
Gupta, Anasuya; Gupta, Sudhiranjan; Young, David et al. (2010) Impairment of ultrastructure and cytoskeleton during progression of cardiac hypertrophy to heart failure. Lab Invest 90:520-30
Gupta, Sudhiranjan; Maitra, Ratan; Young, Dave et al. (2009) Silencing the myotrophin gene by RNA interference leads to the regression of cardiac hypertrophy. Am J Physiol Heart Circ Physiol 297:H627-36
Sivakumar, P; Gupta, Sudhiranjan; Sarkar, Sagartirtha et al. (2008) Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy. Mol Cell Biochem 307:159-67
Gupta, Sudhiranjan; Young, David; Maitra, Ratan K et al. (2008) Prevention of cardiac hypertrophy and heart failure by silencing of NF-kappaB. J Mol Biol 375:637-49
Das, Biswajit; Gupta, Sudhiranjan; Vasanji, Amit et al. (2008) Nuclear co-translocation of myotrophin and p65 stimulates myocyte growth. Regulation by myotrophin hairpin loops. J Biol Chem 283:27947-56
Adhikary, Gautam; Gupta, Sudhiranjan; Sil, Parames et al. (2005) Characterization and functional significance of myotrophin: a gene with multiple transcripts. Gene 353:31-40
Gupta, Sudhiranjan; Young, David; Sen, Subha (2005) Inhibition of NF-kappaB induces regression of cardiac hypertrophy, independent of blood pressure control, in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 289:H20-9
Gupta, Sudhiranjan; Sen, Subha (2005) Role of the NF-kappaB signaling cascade and NF-kappaB-targeted genes in failing human hearts. J Mol Med 83:993-1004

Showing the most recent 10 out of 19 publications