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Journal of Cardiovascular Pharmacology and Therapeutics
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Hyperhomocysteinemic Diabetic Cardiomyopathy: Oxidative Stress, Remodeling, and Endothelial-Myocyte Uncoupling

Suresh C. Tyagi, PhD

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY

Walter Rodriguez, MD

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY

Anuj M. Patel, BS

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY

Andrew M. Roberts, PhD

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY

Jeff C. Falcone, PhD

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY

John C. Passmore, PhD

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY

John T. Fleming, PhD

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY

Irving G. Joshua, PhD

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY

Accumulation of oxidized-matrix (fibrosis) between the endothelium (the endothelial cells embedded among the myocytes) and cardiomyocytes is a hallmark of diabetes mellitus and causes diastolic impairment. In diabetes mellitus, elevated levels of homocysteine activate matrix metalloproteinase and disconnect the endothelium from myocytes. Extracellular matrix functionally links the endothelium to the cardiomyocyte and is important for their synchronization. However, in diabetes mellitus, a disconnection is caused by activated metalloproteinase, with subsequent accumulation of oxidized matrix between the endothelium and myocyte. This contributes to endothelial-myocyte uncoupling and leads to impaired diastolic relaxation of the heart in diabetes mellitus. Elevated levels of homocysteine in diabetes are attributed to impaired homocysteine metabolism by glucose and insulin and decreased renal clearance. Homocysteine induces oxidative stress and is inversely related to the expression of peroxisome proliferators activated receptor (PPAR). Several lines of evidence suggest that ablation of the matrix metalloproteinase (MMP-9) gene ameliorates the endothelial-myocyte uncoupling in diabetes mellitus. Homocysteine competes for, and decreases the PPAR{gamma} activity. In diabetes mellitus, endothelial-myocyte uncoupling is associated with matrix metalloproteinase activation and decreased PPAR{gamma} activity. The purpose of this review is to discuss the role of endothelial-myocyte uncoupling in diabetes mellitus and increased levels of homocysteine, causing activation of latent metalloproteinases, decreased levels of thioredoxin and peroxiredoxin, and cardiac tissue inhibitor of metalloproteinase (CIMP) in response to antagonizing PPAR{gamma}.

Key Words: homocysteine • matrix metalloproteinase • diabetes mellitus • extracellular matrix • edema • seizure • stroke • microvascular permeability

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 10, No. 1, 1-10 (2005)
DOI: 10.1177/107424840501000101
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