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Myocardial fibrosis and TGFB expression in hyperhomocysteinemic rats
Lamia Raaf1, Christophe Noll, Mohamed El Hadi Cherifi
1Univ Paris Diderot-CNRS EAC 4413, unité de Biologie Fonctionnelle et Adaptative, Case 7104, 75205, Paris cedex 13, France.
Insights
Mild hyperhomocysteinemia in rats, induced by methionine, caused heart fibrosis and hypertrophy. This remodeling was linked to altered extracellular matrix degradation and increased transforming growth factor-beta1 (TGFβ1).
Area of Science:
- Cardiovascular Science
- Molecular Biology
- Pathology
Background:
- Hyperhomocysteinemia (elevated homocysteine) is linked to cardiovascular diseases.
- Experimental models show hyperhomocysteinemia causes heart fibrosis and ventricular hypertrophy.
Purpose of the Study:
- To investigate the molecular mechanisms behind cardiac alterations in mild hyperhomocysteinemia.
- To analyze the role of extracellular matrix remodeling in methionine-induced hyperhomocysteinemia.
Main Methods:
- Induction of mild hyperhomocysteinemia in rats via chronic methionine administration.
- Histological analysis (Sirius red staining), histomorphometry, zymography, and immunoblotting.
- Assessment of transforming growth factor-beta1 (TGFβ1), tissue inhibitors of metalloproteinase (TIMP), matrix metalloproteinase (MMP) activity, and JNK activation.
Main Results:
- Methionine-induced hyperhomocysteinemia resulted in interstitial myocardial fibrosis and ventricular cardiomyocyte hypertrophy.
- Increased expression of TGFβ1, TIMP2, and JNK activation was observed.
- Decreased matrix metalloproteinase 2 activity and TIMP1 expression, shifting the TIMP1-MMP1 balance.
- Cardiac remodeling was associated with dysregulated extracellular matrix degradation, partly due to enhanced TGFβ1.
Conclusions:
- Mild hyperhomocysteinemia induces cardiac fibrosis and hypertrophy in rats.
- TGFβ1 upregulation plays a significant role in the observed cardiac remodeling and extracellular matrix dysregulation.
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.
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