Insulin-regulated aminopeptidase: role in cardiovacular disease

The renin-angiotensin system (RAS) is one of the most important hormonal systems regulating both acute and chronic blood pressure. The main effector peptide of the RAS, known as angiotensin II, not only influences blood pressure but also exerts pro-inflammatory and pro-fibrotic effects on organs such as the heart, kidneys and vasculature. These effects are mediated by angiotensin II activating AT1 receptors. Drugs that inhibit AT1 receptor function directly (ARBs) or indirectly (ACE inhibitors) have been the cornerstone for controlling hypertension and hypertension-related end organ damage, although these drugs alone are usually not enough to regress pathological changes in the cardiovascular system that have developed over decades. Increasingly, it is appreciated that a number of angiotensin peptide fragments exert cardiovascular effects that are uniquely different to those of angiotensin II itself. In particular, angiotensin IV has received less attention although this hexapeptide is known to exert vaso-protective effects and has also been shown to inhibit the catalytic site of insulin-regulated aminopeptidase (IRAP). To this end, we are developing novel drugs targeting IRAP that are likely to exert modulatory effects on the cardiovascular system. This overarching project investigates IRAP pharmacology and pathophysiology from a number of perspectives including: - understanding IRAP function in preclinical animal models of cardiovascular disease; - synthesising and developing novel compounds that activate or inhibit IRAP; - elucidating signalling mechanisms; - developing appropriate bioassays to facilitate drug discovery. This project engages with a cross-disciplinary team of researchers including pharmacologists, chemists and physiologists. Experiments range from molecular/cellular/biochemical through to in vivo animal models of cardiovascular disease.