1: The long-term objective of this project is understand the mechanism by which cardiac inhibitor of metalloproteinase (CIMP) shields the heart against oxidative and proteolytic stresses. Previous studies have suggested that with the induction of oxidative stress, there is a decrease in endothelial cell density, activation of metalloproteinase, collagenolysis, and repression of CIMP in cardiac decompensation. This is also highlighted by left ventricle hypertrophy (LVH) and dilatation. The central hypothesis of this project is that CIMP shields the cardiomyocyte against proteolytic and oxidative stress, by decreasing metalloproteinase activity and increasing endothelial nitric oxide. The decreased levels of CIMP trigger nitrotyrosine formation, collagenolysis, LVH and wall stress. Biochemical, molecular, and immunohistochemical techniques, along with ex vivo and in vivo physiological methods, are being used to test our hypothesis. The results are anticipated to elucidate the molecular, cellular, and extracellular mechanism by which lowered levels of CIMP initiate collagenolysis, LVH, and wall stress. Results may also yield insight to possible therapeutic procedures for amelioration of heart disease.

2: The long-term objective of this project is to further the understanding of the role of homocysteine in vessel wall disease and hypertension. Previous studies have indicated a decrease in the bioavailability of endothelial nitric oxide and an increase in the concentration of nitrotyrosine in the aortic wall in hyperhomocysteinemia. Peroxisome proliferator activated receptor (PPAR) is a nuclear receptor which is inversely correlated with the levels of homocysteine. The central hypothesis of this project is that homocysteine antagonizes the activity of PPAR. The induction of PPAR protects the vessel from homocysteine-mediated vascular injury, in part, by increasing endothelial nitric oxide concentration and decreasing the generation of nitrotyrosine and metalloproteinase activity. The results are anticipated to elucidate the molecular, cellular and extracellular mechanism by which homocysteine causes arterial lesions and, hopefully, provide insight to therapeutic ramifications for vessel wall disease.

Research summary statement:

Our goal is to understand the mechanism of cardiovascular-renal remodeling in hypertension and heart failure. Especially, in the absence of endothelial nitric oxide how a tissue dilate? It is widely believed that nitric oxide is the primarily dilatory agent, direct or indirect. However, there are numerous circumstances when nitric oxide is diminished or tissue is without nitric oxide. In this situation the metalloproteinase is activated and dilates the tissue. The initial disruption of extracellular matrix is essential for cell survival. However, prolong disconnect between cell and matrix leads to cell death, necrosis or apoptosis. We employ two approaches 1) create chronic heart failure by volume overload arteriovenous fistula; 2) oxidative condition is created by homocysteine overload, using transgene and promoter dashing (on/off) genomic models. The specific cells responsible for pathogenesis are identified by employing laser dissecting microscope, differential display, and microarray analyses. The biochemical, molecular, and immunohistochemical techniques, along with ex vivo and in vivo physiological methods, are used to test our hypotheses.