The central hypothesis of this project is that chronic endothelin (ET) receptor activation directly contributes to the initiation, progression and severity of the left ventricular (LV) dysfunction and hemodynamic instability which occurs with CHF. Using an animal model of CHF, an isolated myocyte system, and signal transduction experiments, this project has the following specific aims: (1) identify how ET receptor activation during the progression of CHF influences systemic and coronary vascular resistance at rest and with exercise; (2) determine the direct effects of chronic ET receptor activation on myocyte contractile processes and the changes in ET signaling which occur during the progression of CHF; (3) determine the specificity and selectivity of the effects of ET receptor activity on LV and myocyte function during the progression of the CHF process through a series of studies in which neurohormonal modulation and systemic hemodynamics will be controlled by angiotensin converting enzyme inhibition, selective ET receptor blockade, or a combination of both. Through a stepwise and integrative approach, this project will define how the ET receptor signaling mechanism coordinates and contributes to the transition to severe CHF as well as to the identification of a novel therapeutic target to slow the progression of this disease process.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057952-03
Application #
6139237
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1998-01-01
Project End
2001-12-31
Budget Start
2000-01-01
Budget End
2000-12-31
Support Year
3
Fiscal Year
2000
Total Cost
$171,166
Indirect Cost
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Gopinathannair, Rakesh; Etheridge, Susan P; Marchlinski, Francis E et al. (2015) Arrhythmia-Induced Cardiomyopathies: Mechanisms, Recognition, and Management. J Am Coll Cardiol 66:1714-28
Eckhouse, Shaina R; Purcell, Brendan P; McGarvey, Jeremy R et al. (2014) Local hydrogel release of recombinant TIMP-3 attenuates adverse left ventricular remodeling after experimental myocardial infarction. Sci Transl Med 6:223ra21
Graham, Eric M; Atz, Andrew M; McHugh, Kimberly E et al. (2014) Preoperative steroid treatment does not improve markers of inflammation after cardiac surgery in neonates: results from a randomized trial. J Thorac Cardiovasc Surg 147:902-8
Kholmukhamedov, Andaleb; Logdon, Christina; Hu, Jiangting et al. (2014) Cyclosporin A in left ventricular remodeling after myocardial infarction. Am J Physiol Heart Circ Physiol 306:H53-9
Zavadzkas, Juozas A; Stroud, Robert E; Bouges, Shenikqua et al. (2014) Targeted overexpression of tissue inhibitor of matrix metalloproteinase-4 modifies post-myocardial infarction remodeling in mice. Circ Res 114:1435-45
Zile, Michael R; Baicu, Catalin F; Stroud, Robert E et al. (2014) Mechanistic relationship between membrane type-1 matrix metalloproteinase and the myocardial response to pressure overload. Circ Heart Fail 7:340-50
Spinale, Francis G; Stolen, Craig M (2013) Biomarkers and heart disease: what is translational success? J Cardiovasc Transl Res 6:447-8
Spinale, Francis G; Janicki, Joseph S; Zile, Michael R (2013) Membrane-associated matrix proteolysis and heart failure. Circ Res 112:195-208
Eckhouse, Shaina R; Jones, Jeffrey A; Spinale, Francis G (2013) Gene targeting in ischemic heart disease and failure: translational and clinical studies. Biochem Pharmacol 85:1-11
Spinale, Francis G (2013) Epilysin (matrix metalloproteinase-28) joins the matrix metalloproteinase team on the field of postmyocardial infarction remodeling. Circ Res 112:579-82

Showing the most recent 10 out of 67 publications