Grant: Operating Grant - PA: Regional Partnership Program : Manitoba

Cardiovascular disease due to atherosclerosis is the leading cause of death worldwide. Atherosclerosis is an inflammatory process (vessel injury) in the arteries, eventually leading to the fatal blockage of blood supply to the heart (heart attack). One of the earliest detectable abnormalities is the accumulation of white blood cells in the arteries. Those inflammatory cells, particularly monocytes play a key role in the initiation and the development of arterial injury. The recruitment of monocytes to the arterial wall is influenced by inflammatory signals, such as monocyte chemoattractant protein-1 (MCP-1), a very potent chemokine. Liver is the largest internal organ in the body and its ability to produce inflammatory signals has been implicated in cardiovascular disease. Hyperhomocysteinemia is a metabolic disease with elevated levels of homocysteine (an intermediate amino acid) in the blood. It is associated with the increased risk of cardiovascular disease and stroke. Our recent study shows that MCP-1 production is increased in the artery itself as well as in the liver. Strikingly, the increase in liver MCP-1 production correlates very well with the elevated level of MCP-1 in the blood and monocyte recruitment to the arterial wall. We hypothesize that the overproduction of liver MCP-1 during hyperhomocysteinemia leads to a sustained elevation of MCP-1 in the blood. The liver-derived MCP-1 may act synergistically with the artery-generated chemokines, causing an enhancement of monocyte recruitment and leading to arterial injury (atherosclerosis). We aim to investigate the contribution of liver-derived MCP-1 to monocyte recruitment and atherogenesis in animal models that have developed hyperhomocysteinemia and atherosclerosis. Results obtained will allow us and others to design better strategies to specifically target the expression of inflammatory factors not only in the blood vessels but also in other tissues at different stages of cardiovascular disease.