Grant: Operating Grant

High pressure in the arteries that carry blood from the heart to all tissues and organs of the body is a leading cause of illness and death through heart and kidney disease, hardening of the arteries, eye damage and stroke, and accounts for the deaths of more Canadians than any other disease (31% in 2005). Cardiovascular disease costs the Canadian economy more than $22.2 billion every year in physician services, hospitalization costs, lost wages and decreased productivity. Blood pressure is controlled by "smooth muscle cells" in the walls of the blood vessels. When these cells contract (shorten), they reduce vessel diameter and increase blood pressure. Nerves, which terminate at the surface of smooth muscle cells, release chemicals, which act on the membrane (surface) of the smooth muscle cells to reverse the electric charge distribution across the cell membrane, allowing the entry of calcium, which triggers contraction (shortening). The molecular mechanism whereby calcium triggers contraction involves activation of an enzyme (a protein catalyst) called "myosin light chain kinase". We made the important discovery that this simple mechanism is only part of the story; the challenge now is to complete the story. We discovered that calcium also activates a pathway (a molecular cascade) leading to inhibition of the enzyme "myosin light chain phosphatase", which reverses the action of myosin light chain kinase. The objective of this project is to explain, at the molecular level, how calcium leads to inhibition of myosin light chain phosphatase, and how the pathway is altered in animal models of hypertension. This work will lead to the identification of novel drug targets. Given the high incidence and serious impact of hypertension, combined with the side effects of existing blood pressure-lowering drugs, such as calcium channel blockers, ACE inhibitors and beta blockers, it is critical that such novel drug targets be identified.