Reversal of endocardial endothelial dysfunction by folic acid in homocysteinemic hypertensive rats

Abstract

The role of L- and D-isomers of homocysteine (Hcy) in vascular versus endocardial endothelial (EE) remodeling and function is not well understood. The hypothesis is that Hcy decreases EE cell density by activating matrix metalloproteinase (MMP) and by inducing left ventricular hypertrophy (LVH) in homocysteinemic hypertensive rats (HHR). And L- and D-isomers of Hcy have differential effects in vessel and myocardium. We used: 1) spontaneously hypertensive rats (SHR) in which endogenous total homocyst(e)ine (tHcy) levels are moderately high (18 micromol/L); 2) control age- and sex-matched normotensive Wistar rats (NWR) in which tHcy levels are normal (4 micromol/L); to create hyperhomocyst(e)inemia, 32 mg/day Hcy was administered for 12 weeks in 3) SHR (SHR-H), and in 4) NWR (NWR-H) rats; 5) endogenous tHcy levels were reduced (from 18 to 12 micromol/L) in SHR by folic acid administration (SHR-F). Plasma tHcy levels were measured by HPLC and spectrophometric methods. The MMP activity, measured by zymography, is increased by chronic Hcy administration, and folic acid treatment decreases MMP activity. The collagen and transforming growth factor-beta1 (TGF-beta1), measured by reverse transcriptase-polymerase chain reaction, are increased by Hcy. Folic acid treatment decreases collagen expression and increases TGF-beta1. In vivo LV function was measured in anesthetized rats by a catheter in the left ventricle. The partial decrease in tHcy levels and no change in arterial pressure in SHR after folic acid administration, suggested that folic acid decreases one of the L- or D-isomer of Hcy, which is not responsible for an increase in arterial pressure, but may be responsible for myocardial dysfunction. The chronic Hcy administration decreases EE function in NWR and SHR. The treatment of folic acid in SHR improves LVH and EE function. Folic acid improves cardiac remodeling and EE function by decreasing one of the D- or L-isomer of Hcy and by decreasing MMP activity in HHR. These results may suggest a differential role of L- and D-isomers in vascular versus cardiac remodeling.