) 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. The purpose of the present study is test the hypothesis that myocyte contractile activity per se is a major stimulus of cardiomyocyte growth and function. The experimental approach is designed to identify the molecular mechanisms involved in the transduction of the contractile signal to the nucleus. Data from previous in vitro and in vivo studies that examined the transcriptional regulation of the alpha-myosin heavy chain (alpha-MHC) gene allow them to integrate the nuclear changes within the overall cellular response to the changes in hemodynamic load. This application addresses four specific aims: (1) identification of a transcription factor(s) that binds to a cis-acting element at -47 bp of the transcriptional start site of the alpha-MHC gene, designated hemodynamic response element (HME), that is both necessary and sufficient to confer contractile responsiveness to this promoter in cardiac myocytes. This nuclear protein (designated HRP) will be cloned from a cardiomyocyte expression library by its ability to bind to the HME sequence and to activate the alpha-MHC promoter; (2) study the mechanisms by which the contractile stimulus regulates the transcriptional activity of HRP by determining whether its activity is modulated by phosphorylation, determine its DNA binding characteristics, and its dimerization properties in response to the contractile stimulus; (3) study the contractile-induced signaling pathway in which protein kinase C-zeta plays a role in the phosphorylation and activation of HRP; and (4) determine the in vivo function of HRP by using viral vector systems to deliver the gene into the hemodynamically unloaded, heterotopically transplanted heart, that undergoes atrophy and decreased alpha-MHC expression. These studies will advance the understanding of the molecular pathways by which workload regulates cardiac growth and function, and potentially lead to novel genetic therapies of disorders of cardiac growth leading to pathologic hypertrophy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research (K02)
Project #
1K02HL003775-01
Application #
2450764
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (O1))
Project Start
1998-08-05
Project End
2003-07-31
Budget Start
1998-08-05
Budget End
1999-07-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
North Shore University Hospital
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Kenessey, Agnes; Ojamaa, Kaie (2005) Ligand-mediated decrease of thyroid hormone receptor-alpha1 in cardiomyocytes by proteosome-dependent degradation and altered mRNA stability. Am J Physiol Heart Circ Physiol 288:H813-21
McMahon, Clarie K; Klein, Irwin; Ojamaa, Kaie (2003) Interleukin-6 and thyroid hormone metabolism in pediatric cardiac surgery patients. Thyroid 13:301-4
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
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Ojamaa, K; Kenessey, A; Klein, I (2000) Thyroid hormone regulation of phospholamban phosphorylation in the rat heart. Endocrinology 141:2139-44
Ojamaa, K; Kenessey, A; Shenoy, R et al. (2000) Thyroid hormone metabolism and cardiac gene expression after acute myocardial infarction in the rat. Am J Physiol Endocrinol Metab 279:E1319-24
Ojamaa, K; Sabet, A; Kenessey, A et al. (1999) Regulation of rat cardiac Kv1.5 gene expression by thyroid hormone is rapid and chamber specific. Endocrinology 140:3170-6