The applicant proposes to test the following hypothesis: The development of pressure overload hypertrophy induces nitric oxide synthase (iNOS) and results in elevated myocardial nitric oxide (NO). The elevated NO leads to increased peroxynitrite induced myocardial injury, specifically in the mitochondria, resulting in increased susceptibility to ischemic injury and leading to CHF. The applicant will use a rat model of aortic banding which causes pressure overload hypertrophy leading to CHF. Changes in NO and iNOS will be characterized over time in this model and related to functional alterations using the isolated perfused rat heart, isolated cardiac myocytes and mitochondria. The degree of peroxynitrite injury to the myocardium will be determined by immunohistochemistry and western blots to determine the degree of tyrosine nitration. Levels of NO and iNOS will be manipulated pharmacologically in order to assess their role in the development of hypertrophy and CHF. In addition, hearts will be subjected to ischemic injury and peroxynitrite infusion in order to identify specific metabolic alterations which may manifest under conditions of stress.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058895-02
Application #
2901341
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1998-04-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Brookes, P S; Zhang, J; Dai, L et al. (2001) Increased sensitivity of mitochondrial respiration to inhibition by nitric oxide in cardiac hypertrophy. J Mol Cell Cardiol 33:69-82
Dai, L; Brookes, P S; Darley-Usmar, V M et al. (2001) Bioenergetics in cardiac hypertrophy: mitochondrial respiration as a pathological target of NO*. Am J Physiol Heart Circ Physiol 281:H2261-9
Shiva, S; Brookes, P S; Patel, R P et al. (2001) Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase. Proc Natl Acad Sci U S A 98:7212-7