In addition to enhanced arterial blood pressure, hypertensives have inflammatory mechanisms that cause microvascular and parenchymal cell dysfunction, apoptosis, and lesion formation. It is our long-term objective to identify these inflammatory mechanisms in the microcirculation where early detection is possible before development of overt clinical signs. We hypothesize that besides enhanced oxygen radical formation, the microcirculation of spontaneously hypertensive rats (SHRs) exhibits a greatly enhanced protease activity with over-expression of matrix metalloproteinases. The presence of proteolytic enzymes in the SHR causes cleavage of the extracellular domain of membrane receptors and loss of cell function, for example cleavage of the extracellular domain of the insulin receptor a or membrane adhesion molecule CD18 with loss of the ability to bind insulin and facilitate glucose transport or leukocyte adhesion, i.e. insulin resistance and immune suppression, respectively. We provide preliminary evidence that chronic MMP blockade in the SHR reduces receptor cleavage and annihilates insulin resistance, CD18 cleavage, and normalizes the blood pressure, oxygen free radical formation, and apoptosis.
Our Specific Aims are (1) to measure the activity and expression of MMPs in the microcirculation of the SHR and its normotensive controls (Wistar Kyoto rat and Wistar Rat);to measure the level of microvascular cell dysfunction and organ injury after blockade of the proteases;and identify mechanisms for activation of MMP preforms;(2) to determine the level of receptor cleavage and its role in microvascular cell dysfunction in the SHR and its controls;to measure membrane density before and after chronic MMP inhibition;to measure the ability of SHR plasma to acutely cleave receptors in-vitro on naive cells from the normotensive Wistar strain and the associated cell dysfunction;(3) determine signaling pathways in the SHR that lead to MMP expression in microvascular endothelium, leukocytes, and interstitial cells that involve superoxide formation and nuclear factor NFkB activation. We will apply new experimental techniques to measure protease activity in a living microcirculation, measure protein and message levels of proteases in a complete microvascular network with high and low pressure domains as a tool to identify pressure mediated mechanisms. We will determine to what degree blockade of protease activity prevents receptor cleavage and cell dysfunctions in the SHR. We will identify specific enzymatic activity in the microcirculation as therapeutic target in the future to attenuate inflammatory processes in hypertensives. The research program serves the first time to unify a diverse set of pathogenic mechanisms in the SHR under one mechanistic hypothesis and at the same time open the opportunity for new therapeutic approaches.
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