- Project 1 Increased cardiac Ang II activity-as a result of upregulated Ang II formation in the intracellular or interstitial compartment acting via autocrine or paracrine mechanisms- contributes to cardiac hypertrophic remodeling, arrhythmias, and fibrosis. RAS inhibitors are less effective in blocking Ang II-mediated adverse cardiac remodeling because Ang II production in cardiac myocytes follows a non-canonical pathway through the processing of angiotensinogen (Aogen) into the dodecapeptide intermediate substrate Ang-(1-12). We further showed that Ang-(1-12) metabolism between rodents and humans is that chymase but not ACE converts Ang- (1-12) directly into Ang II in human heart tissue and that this process may include an additional step in which human Aogen may be processed into a newly identified precursor Ang-(1-25) prior to conversion into Ang-(1- 12). The human form of ? cardiac chymase, either expressed in cardiomyocytes or incorporated into these cells from activated mast cells, is the enzyme producing Ang II from Ang-(1-12) and likely Ang-(1-25). Pilot studies suggest a role for kallikrein as the enzyme cleaving Ang-(1-12) from Aogen. On these bases, Project 1 poses the hypothesis that Ang II-mediated adverse cardiac remodeling results from the processing of intermediate forms of Aogen-derived peptides through the hydrolytic activity of intracellularly formed or incorporated chymase. Furthermore, we propose that these biotransformation steps are species-specific. To achieve these objectives we will determine:
Aim 1, the compartmentalization and role of kallikrein or a kallikrein family member enzyme in the production of Ang-(1-12) from cardiac Aogen in WKY and SHR and its potential hydrolytic activity in cardiac Ang-(1-12) production in a transgenic rat model expressing the genes from human Aogen [TGR(hAGT)L1623];
Aim 2, the role of Ang-(1-12) and Ang-(1-25) as substrates for cardiomyocyte Ang II production in WKY and SHR versus TGR(hAGT)L1623 rats;
Aim 3, the hemodynamic and RAS profile and the enzymes accounting for the expression of Ang-(1-25) and Ang-(1-12) in TGR(hAGT)L1623. We will also assess whether the chymase-driven cardiac Ang II pathway is influenced by species-specificity through the crossing of the human Aogen transgenic rat with a rat expressing the genes for human chymase. Our work will reveal new therapeutic approaches to hypertensive cardiac hypertrophy and fibrosis that are based on non- canonical cardiac Ang II formation.
- Project 1 Clinical studies and assessment of outcomes in large clinical trials have not demonstrated meaningful differences in the reduction of cardiovascular outcomes achieved by renin angiotensin system (RAS) inhibitors and other antihypertensive agents. Demonstration that Ang II trophic, profibrotic, and arrhythmic actions in the heart result from processing enzymes and intermediate substrates that are not prevented by ACE inhibitors or Ang II receptor blockers will significant therapeutic implications.
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