The heart responds to various hemodynamic and humoral stimuli by changes in myocyte size and function. Left ventricular hypertrophy such as arises from hypertension or valvular disease is a sensitive predictor for morbidity and mortality due to myocardial dysfunction. In the present application we propose to test the hypothesis that myocyte contractile activity per se regulates the transcription of the (alpha)-myosin heavy chain (alpha-MHC) gene. We have identified a cis-acting element at -47 bp from the transcription initiation site, designated hemodynamic response element (HME), that is both necessary and sufficient to confer contractile responsiveness in spontaneously contracting cardiomyocytes in culture. The HME contains an E-box motif whose binding protein (designated HRP) is antigenically related to USF (upstream stimulatory factor). We propose to clone HRP from a neonatal rat cardiomyocyte expression library by its ability to bind specifically to the HME sequence. Expression studies of the cloned HRP is cultured cardiac myocytes will confirm its role in contractile-mediated (alpha-)-MHC transcription. In vitro studies will determine its dimerization, DNA binding and transcription activation properties, and whether phosphorylation of HRP occurs in response to the mechanogenic stimulus. The role PKC(Z) in the signal transduction pathway and its potential localization to the nucleus will be determined. We propose to study the combinatorial effects of thyroid hormone (TH) and contractile activity on transcriptional regulation of the (alpha)-MHC gene to understand the rapid induction of this gene at birth when both TH and cardia hemodynamics are changing. The interaction of these activators with general transcription factors (TATA box binding protein and TAFs) will be studied to determine the molecular basis of workload- and hormone-regulated (alpha)-MHC transcription. To verify the transcriptional role of HRP in vivo we propose to overexpress HRP in the hemodynamically unloaded heart to directly assess its effect on (alpha)-MHC promoter activity and to determine whether PKC(Z) phosphorylation of HRP is required for its transcriptional activation. These studies will advance our understanding of the molecular pathways of workload regulated cardiac growth and function.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Cardiovascular and Pulmonary Research A Study Section (CVA)
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North Shore University Hospital
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Ojamaa, Kaie (2010) Signaling mechanisms in thyroid hormone-induced cardiac hypertrophy. Vascul Pharmacol 52:113-9
McMahon, Clarie K; Klein, Irwin; Ojamaa, Kaie (2003) Interleukin-6 and thyroid hormone metabolism in pediatric cardiac surgery patients. Thyroid 13:301-4
Danzi, Sara; Ojamaa, Kaie; Klein, Irwin (2003) Triiodothyronine-mediated myosin heavy chain gene transcription in the heart. Am J Physiol Heart Circ Physiol 284:H2255-62
Xiao, Qianxun; Kenessey, Agnes; Ojamaa, Kaie (2002) Role of USF1 phosphorylation on cardiac alpha-myosin heavy chain promoter activity. Am J Physiol Heart Circ Physiol 283:H213-9
Sun, Z Q; Ojamaa, K; Nakamura, T Y et al. (2001) Thyroid hormone increases pacemaker activity in rat neonatal atrial myocytes. J Mol Cell Cardiol 33:811-24
Chowdhury, D; Ojamaa, K; Parnell, V A et al. (2001) A prospective randomized clinical study of thyroid hormone treatment after operations for complex congenital heart disease. J Thorac Cardiovasc Surg 122:1023-5
Shenoy, R; Klein, I; Ojamaa, K (2001) Differential regulation of SR calcium transporters by thyroid hormone in rat atria and ventricles. Am J Physiol Heart Circ Physiol 281:H1690-6
Klein, I; Ojamaa, K (2001) Thyroid hormone: targeting the vascular smooth muscle cell. Circ Res 88:260-1
Ojamaa, K; Kenessey, A; Klein, I (2000) Thyroid hormone regulation of phospholamban phosphorylation in the rat heart. Endocrinology 141:2139-44
Ojamaa, K; Klein, I; Sabet, A et al. (2000) Changes in adenylyl cyclase isoforms as a mechanism for thyroid hormone modulation of cardiac beta-adrenergic receptor responsiveness. Metabolism 49:275-9

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