Substance P-Mediated Cardiovascular Inflammation

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DESCRIPTION (provided by applicant): This proposal addresses the pathobiology of inflammation of the heart due to neurogenic peptides, particularly substance P (SP). Recent data have provided support for the neuronal NMDA receptor contribution to the cardiovascular inflammatory process due to Mg-deficiency (MgD). In addition concurrent intestinal inflammation may enhance the later phase of the cardiomyopathy via activation of PMNs and endotoxin signaling. These recent findings provide the basis for the following Aims and collaborations: Aim 1. Assess the contribution of NMDA-receptor activation to the early SP elevation and how SP can be modulated during the acute "trigger phase" of dietary MgD. Aim 2. Determine the extent of NK-1 receptor expression and proinflammatory/oxidative response in the circulation and cardiac tissues during MgD. Aim 3. (with Dr. Shea-Donohue) Assess if MgD induces a neurogenic inflammation in the gut that is associated with altered intestinal function, enhanced mucosa barrier permeability, and increased sensitivity to oxidative stress; assess if systemic inflammatory response syndrome (SIRS) or endotoxemia contribute significantly to "cardiac inflammation/cardiomyopathy at a distance." Aim 4. Assess whether defects in baseline contractility of perfused rat heads develops during the late response phase of MgD and if in vivo interventions (MK-801, NK-1 receptor blocker, RTX, phosphoramidon, antibiotics) have a significant impact on cardiac baseline contractility dysfunction and tolerance to ltR stress. Aim 5. Assess if proinflammatory effects of MgD are altered in LPS-resistant vs. sensitive mice. We will employ a combination of immunohistochemical and molecular/protein biology (RT-PCR, Western-blotting) techniques, and gene chip technology to assess relevant genetic expression; more traditional biochemical (tissue glutathione and antioxidant status, plasma isoprotane level) and biophysical (ESR-spin trapping of free radicals and NO in isolated perfused heads) approaches will also be used.The hypotheses to be pursued in the Research Plan are outlined in Illustration 1. The potential relevance of clinical MgD to proinflammatory events in heart failure and other disease processes is addressed in the text.