Hypothesis regarding the pathophysiological role of alternative pathways of angiotensin II formation in atherosclerosis

The renin-angiotensin system has been studied and recognized as one of the major blood pressure-regulating systems for the past century. In the last q uarter century, however, many alternative pathways of angiotensin II format ion have been found, and among them, chymase has been a focus of interest b ecause of its specificity and potency in the human cardiovascular system. C hymase evidently is not involved in functional regulation of blood pressure at least in the short term. but evidence is accumulating that it may be in volved in structural remodeling of the cardiovascular system. We found incr eased vascular chymase activity in atherosclerotic lesions of the human aor ta as well as in cardiac remodeling after myocardial infarction. We found a significant positive correlation between serum total or LDL cholesterol le vels and arterial chymase-dependent angiotensin II-forming activity in pati ents who were undergoing coronary artery bypass operation, suggesting that high serum cholesterol may trigger upregulation of vascular chymase and fac ilitate the development of atherosclerosis. This hypothesis was tested in S yrian hamsters fed a high cholesterol diet containing 0.5% cholesterol: A m arked lipid deposition in the aortic cusp developed and the plasma choleste rol levels were positively correlated with aortic chymase activity. An oral ly active nonpeptide chymase inhibitor almost canceled this lipid depositio n. These clinical and experimental data indicated an association between ch olesterol and vascular chymase upregulation that may facilitate the develop ment of atherosclerosis.