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.

Relationship Between Plasma Homocysteine Levels and Congestive Heart Failure in Patients With Acute Myocardial Infarction Homocysteine and Congestive Heart Failure

“…29) Finally, the development of myocardial fibrosis and matrix metalloproteinase activity was increased in rats with high levels of homocysteine. [26][27] In this study, however, no differences in the peak creatine kinase or troponin T levels, which indicate infarct size, were observed between the two groups. Therefore, heart failure was caused not only by direct myocardial damage resulting from AMI, but also occurred after AMI associated with potential cardiac dysfunction, including left ventricular remodeling, induced by elevated plasma homocysteine levels.…”

“…However, possible causes include vascular endothelial dysfunction, [17][18][19][20][21][22] smooth muscle cell growth, [23][24][25] and an increase in blood clotting activity in vascular walls. 26,27) Elevated homocysteine levels may promote heart failure through 4 potential mechanisms. First, as described above, an elevated homocysteine level is widely considered a risk factor for coronary arteriosclerosis and myocardial infarction.…”

Effects of Folic Acid and Magnesium on the Production of Homocysteine-Induced Extracellular Matrix Metalloproteinase-2 in Cultured Rat Vascular Smooth Muscle Cells

“…31 Miller et al showed that folic acid treatment reduced, in part, the MMP activity at 66 and 72 kD (MMP-2). 32 Narin et al concluded that even folic acid treatment alone may be sufficient for decreasing the negative effects of homocysteine. 33 Hagar suggested that hyperhomocysteinemia aggravates myocardial infarction via oxidative stress mechanisms and that lowering the homocysteine level with folic acid and vitamin B12 can ameliorate the detrimental effects of hyperhomocysteinemia and may reduce the risk of myocardial infarction.…”

Gelatinase B(MMP-9) an apoptotic factor in diabetic transgenic mice

“…In addition, the cardiac ring preparation separated the effect of LV from RV. To determine the specific regional differences in contractile function, the rings can be prepared to include or to exclude the homogenous or inhomogeneous regions of the transmural myocardial wall [31,32,33,34]. The "deli" shaped LV rings were mounted in a tissue myobath.…”