Myocardial fibrosis and TGFB expression in hyperhomocysteinemic rats

Abstract

Hyperhomocysteinemia, characterized by an elevated plasma homocysteine concentration, leads to several clinical manifestations and particularly cardiovascular diseases. Experimental models of hyperhomocysteinemia revealed several tissue injuries including heart fibrosis and ventricular hypertrophy. In order to analyze the molecular mechanisms link to these morphological alterations, a mild hyperhomocysteinemia was induced in rats via a chronic methionine administration. Effects of methionine administration were examined by histological analysis with Sirius red staining, histomorphometric analysis, zymography, and immunoblotting. Hyperhomocysteinemia due to methionine administration produces an interstitial myocardial fibrosis and a ventricular cardiomyocyte hypertrophy, which were associated with increased expression of transforming growth factor-beta1 (TGFβ1), tissue inhibitors of metalloproteinase (TIMP) 2, and JNK activation. However, the matrix metalloproteinase 2 activity was decreased in the hearts of hyperhomocysteinemic rats. Moreover, the TIMP1 protein expression was decreased, and the TIMP1-MMP1 balance was shifted. Remodeling in cardiac tissue observed in rat model of mild hyperhomocysteinemia is associated with a dysregulation in extracellular matrix degradation which results, at least in part, from enhancement of TGFβ1 level.

Intermedin_1–53 Protects Against Myocardial Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Inflammation Induced by Homocysteine in Apolipoprotein E-Deficient Mice

“…Activated TGF- β 1 can induce myofibroblast formation and increase extracellular matrix deposition by upregulating collagen synthesis and inhibiting matrix degradation, which leads to myocardial fibrosis 23) . In addition, NF- κ B and JNK pathways can be activated by Hcy 7, 44) . Here, we found that IMD 1–53 inhibited the Hcy-increased levels of inflammatory molecules such as TNF- α , MCP-1, IL-6, and IL-1 β in the ApoE-/- mouse myocardium treated with Hcy, which was further confirmed in CFs.…”

“…Hcy is an amino acid-containing sulfydryl from methionine. The normal concentration of circulating Hcy is approximately 10 µmol/l, while the level of Hcy in hyperhomocysteinemia (HHcy) exceeds 15 µmol/l 7) . Plasma Hcy level was closely relative to left ventricular myocardial hypertrophy and left ventricle mass fraction 8, 9) .…”

“…Plasma Hcy level was closely relative to left ventricular myocardial hypertrophy and left ventricle mass fraction 8, 9) . In addition, Hcy led to several heart morphological alterations including myocardial fibrosis and myocardial hypertrophy in vivo and in vitro 7, 10–12) .…”

Selective homocysteine-lowering gene transfer attenuates pressure overload-induced cardiomyopathy via reduced oxidative stress

“…Mild hyperhomocysteinemia induced in rats via chronic methionine administration or in heterozygous cystathionine--synthase (Cbs) deficient mice induces cardiomyocyte hypertrophy and interstitial fibrosis [9,10]. However, an analysis of in vivo cardiac function has not been performed in these models.…”

Mild hyperhomocysteinemia alters extracellular adenine metabolism in rat brain

“…Mild hyperhomocysteinemia, characterized by an elevated plasma Hcy concentration between 15 and 30 lmol/L (Raaf et al, 2011), is common in many populations whereas can be caused by thermolabile variant of methylenetetrahydrofolate reductase, vitamin deficiencies, drug treatment, aging, smoking, alcohol consumption, or can be secondary to systemic diseases such as insulin-dependent diabetes and hypothyroidism (Jacques et al, 2001;De Bree et al, 2002;Castro et al, 2006;Selhub, 2006;Troen et al, 2008). Furthermore, studies have shown that mild hyperhomocysteinemia is a risk factor to cardiovascular (De Bree et al, 2002;Huang et al, 2008) and neurodegenerative diseases (Obeid and Herrmann, 2006;Minagawa et al, 2010;Herrmann and Obeid, 2011).…”