The Renin-Angiotensin System and Cardiovascular Disease

Cardiovascular disease continues to be the leading cause of death and morbidity in America. The most pervasive cause of cardiovascular disease is high blood pressure (hypertension) which damages blood vessels and the heart leading to heart attacks, stroke and kidney failure. A leading cause of hypertension is the renin-angiotensin system (RAS). The active peptide hormone of the system, angiotensin II constricts blood vessels increasing resistance to blood flow by acting on a class of receptors known as the AT-1 subtype. This stresses the blood-pumping ability of the heart. It also promotes atherosclerosis, cardiac fibrosis (stiffening of the heart) and retention of fluid. It also acts in the brain to cause thirst, salt appetite and increased sympathetic nervous system activity which further stresses the heart and blood vessels. Several classes of drugs which either block formation of angiotensin II or block the AT-1 receptor have been developed to counteract the RAS. They are widely used clinically with good efficacy. However, hypertension continues to be a major health problem for many, and improved strategies for combating this disorder are needed. The discovery that other angiotensin peptides, e.g., angiotensin III, angiotensin IV and angiotensin (1-7), have activity on their own, and can be formed by specific enzymes, e.g., angiotensin-converting enzyme-2 (ACE-2), as well as the discovery of new receptors and binding proteins for angiotensin peptides, e.g., the AT-4 receptor, the mas oncogene protein and a novel angiotensin II / angiotensin III binding protein offer the potential for new therapeutic approaches to counteract hypertension.