Emerging new evidence from both human studies and animal models implicate endothelin (ET) participation in variety of pathogenesis, including myocardial fibrosis. Cardiac fibrosis is characterized by an increased accumulation of type I collagen. It has been demonstrated that the activated (phenotypically transformed) fibroblast-like cells termed """"""""myofibroblasts"""""""" (myoFb), which appear at the site of injury are responsible for expressing contractile protein (alpha smooth muscle actin) and type I collagen during tissue repair and remodeling. Recently, we have identified that myoFb isolated from the site of myocardial infarction, express high levels of TGFbeta/1 and also serve as a non-endothelial source of ET. The mechanisms involved in regulating ET production and its induction of extracellular matrix collagen gene expression by these cells is unclear. Proposed investigations will provide important insights into the new emerging pathophysiological roles of this vasoactive peptide. We will use myoFb to study the specific cellular signaling and molecular mechanisms of endothelin expression and its mechanism of action, including its possible cross-regulation with TGFbeta/1 in modulating collagen gene expression. An understanding of the complex cascade of cellular and molecular mechanisms of ET peptide may have important therapeutic implications.
The specific aims are as follows: 1. to confirm de novo ET generation in myoFb, including its regulation of expression by ET itself or by TGF-beta/1; 2. to identify cis-acting elements and their trans- acting factors in the promotion of type I collagen [alpha1(I)] gene that respond to ET and TGFbeta/1. In these studies, the specific sequences involved in the alpha1(I) promoter will be identified by reporter gene assays; 3. to examine ET-receptor signaling pathway(s), particularly protein kinase C (PKC) and protein tyrosine kinase (PTK) involved in the induction of collagen gene expression; and 4. to examine the relationship between ET and TGF-beta/1 in the type I collagen expression induced by ET. To achieve this, we will investigate the role of trans-acting factors for ET and TGF-beta/1 in the alpha1(I) expression. The long term goals of this research is to understand the emerging new effects of ET and its interplay with growth factors such as TGF-beta/1 in cardiac tissue repair and pathologic remodeling that accompanies various forms of heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060047-03
Application #
6183859
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1999-04-01
Project End
2003-03-31
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
3
Fiscal Year
2000
Total Cost
$143,841
Indirect Cost
Name
East Carolina University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Greenville
State
NC
Country
United States
Zip Code
27858
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Chintalgattu, Vishnu; Katwa, Laxmansa C (2009) Role of protein kinase C-delta in angiotensin II induced cardiac fibrosis. Biochem Biophys Res Commun 386:612-6
Harris, Gregory S; Lust, Robert M; DeAntonio, Jonathan H et al. (2008) PPAR-gamma expression in animals subjected to volume overload and chronic Urotensin II administration. Peptides 29:795-800
Harris, Gregory S; Lust, Robert M; Katwa, Laxmansa C (2007) Hemodynamic effects of chronic urotensin II administration in animals with and without aorto-caval fistula. Peptides 28:1483-9
Chintalgattu, Vishnu; Harris, Gregory S; Akula, Shaw M et al. (2007) PPAR-gamma agonists induce the expression of VEGF and its receptors in cultured cardiac myofibroblasts. Cardiovasc Res 74:140-50
Morrison, R Ray; Teng, Bunyen; Oldenburg, Peter J et al. (2006) Effects of targeted deletion of A1 adenosine receptors on postischemic cardiac function and expression of adenosine receptor subtypes. Am J Physiol Heart Circ Physiol 291:H1875-82
Murashov, Alexander K; Pak, Elena S; Katwa, Laxmansa C (2005) Parallel development of cardiomyocytes and neurons in embryonic stem cell culture. Biochem Biophys Res Commun 332:653-6
Chintalgattu, Vishnu; Katwa, Laxmansa C (2004) Role of protein kinase Cdelta in endothelin-induced type I collagen expression in cardiac myofibroblasts isolated from the site of myocardial infarction. J Pharmacol Exp Ther 311:691-9
Islamov, Rustem R; Chintalgattu, Vishnu; Pak, Elena S et al. (2004) Induction of VEGF and its Flt-1 receptor after sciatic nerve crush injury. Neuroreport 15:2117-21
Katwa, Laxmansa C (2003) Cardiac myofibroblasts isolated from the site of myocardial infarction express endothelin de novo. Am J Physiol Heart Circ Physiol 285:H1132-9

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