Hyperhomocyst(e)inemia induces multiorgan damage

Hyperhomocyst(e)inemia has been associated with the development of hyperten sion, stroke, and cardiovascular, cerebral/neuronal, renal, and liver disea ses. To test the hypothesis that homocyst(e)ine plays an integrated role in multiorgan injury in hypertension, we employed: (1) spontaneously hyperten sive rats (SHR) in which endogenous homocyst(e)ine levels are moderately hi gh (18.1 +/- 0.5 muM); (2) control age- and sex-matched Wistar Kyoto (WKY) rats in which homocyst(e)ine levels are normal (3.7 +/- 0.3 CIM) To create the pathophysiological condition of hyperhomocyst(e)inemia, 20mg/day homocy st(e)ine was administered for 12 weeks in (3) SHR (SHR-H) and in (4) WKY (W KY-H) rats, (5) Endogenous homocyst(e)ine levels were reduced slightly but not significantly from 18.1 +/- 0.5 muM to 12.5 +/- 0.7 muM in SHR by folic acid administration (SHR-F), Plasma and tissue levels of homocyst(e)ine we re determined by HPLC and spectrophotometric methods. Plasma and sympatheti c ganglion (neuronal) matrix metalloproteinase (MMP) activity was measured by zymography. Activity of neuronal MMP was increased in hyperhomocyst(e)in emic rats as compared with controls. Mean arterial pressure (mmHg) was 95 /- 5, 126 +/- 8,157 +/- 10, 188 +/- 5, and 165 +/- 12 in WKY, WKY-H, SHR, S HR-H, and SHR-F, respectively. Urinary protein (mg/day) was 0.11 +/- 0.03. 0.88 +/- 0.22, 0.47 +/- 0.10, 0.89 +/- 0.21, and 0.81 +/- 0.21 in WKY, WKY- H, SHR, SHR-H, and SHR-F, respectively, as measured by the Bio-Rad dye bind ing assay. The relationships between increased arterial pressure, plasma ho mocyst(e)ine, and urinary protein were delineated. Plasma and neuronal crea tinine phosphokinase (CK) isoenzymes were measured by agarose gel electroph oresis. All three CK isoenzymes, i.e., MM, MB, and BE, specific for skeleta l, cardiac, and nerve tissue, respectively, were induced following 12 weeks hyperhomocyst(e)inemia. suggesting multiorgan injury by homocyst(e)ine. Ho mocyst(e)ine induces endocardial endothelial cell (capillary) apoptosis and may reduce capillary cell density. Structural damage to aorta, myocardium. kidney, and renal-ureter was analyzed by histology. Results suggested an i ntegrated physiological role of homocyst(e)ine in injury to the endothelial /epithelial cell lining in the respective organs.