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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Renal Study Section (CVB)
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Lathrop, David A
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George Washington University
Internal Medicine/Medicine
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United States
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Mak, I Tong; Kramer, Jay H; Chmielinska, Joanna J et al. (2015) EGFR-TKI, erlotinib, causes hypomagnesemia, oxidative stress, and cardiac dysfunction: attenuation by NK-1 receptor blockade. J Cardiovasc Pharmacol 65:54-61
Weglicki, William B; Kramer, Jay H; Spurney, Christopher F et al. (2012) The EGFR tyrosine kinase inhibitor tyrphostin AG-1478 causes hypomagnesemia and cardiac dysfunction. Can J Physiol Pharmacol 90:1145-9
Mak, I Tong; Chmielinska, Joanna J; Kramer, Jay H et al. (2011) Loss of neutral endopeptidase activity contributes to neutrophil activation and cardiac dysfunction during chronic hypomagnesemia: Protection by substance P receptor blockade. Exp Clin Cardiol 16:121-4
Weglicki, William B; Mak, Iu Tong; Chmielinska, Joanna J et al. (2010) The role of magnesium deficiency in cardiovascular and intestinal inflammation. Magnes Res 23:S199-206
Weber, Karl T; Weglicki, William B; Simpson, Robert U (2009) Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium. Cardiovasc Res 81:500-8
Kramer, Jay H; Spurney, Christopher; Iantorno, Micaela et al. (2009) Neurogenic inflammation and cardiac dysfunction due to hypomagnesemia. Am J Med Sci 338:22-7
Weglicki, William B; Chmielinska, Joanna J; Tejero-Taldo, Isabel et al. (2009) Neutral endopeptidase inhibition enhances substance P mediated inflammation due to hypomagnesemia. Magnes Res 22:167S-173S
Mak, I T; Kramer, J H; Chmielinska, J J et al. (2008) Inhibition of neutral endopeptidase potentiates neutrophil activation during Mg-deficiency in the rat. Inflamm Res 57:300-5
Scanlan, Bradford J; Tuft, Blaine; Elfrey, Justin E et al. (2007) Intestinal inflammation caused by magnesium deficiency alters basal and oxidative stress-induced intestinal function. Mol Cell Biochem 306:59-69
Tejero-Taldo, Maria Isabel; Kramer, Jay Harlan; Mak, Iu Tong et al. (2006) The nerve-heart connection in the pro-oxidant response to Mg-deficiency. Heart Fail Rev 11:35-44

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