Homocysteine-mediated activation and mitochondrial translocation of calpain regulates MMP-9 in MVEC
| Autor: | Neetu Tyagi, Mahavir Singh, Hong Zhang, Brooke C. Henderson, Dorothea S. Rosenberger, Utpal Sen, Karni S. Moshal, Suresh C. Tyagi |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Hyperhomocysteinemia Homocysteine Physiology Mitochondrion Biology Matrix metalloproteinase Gene Expression Regulation Enzymologic Extracellular matrix chemistry.chemical_compound Cytosol Physiology (medical) medicine Animals Rats Wistar Cells Cultured Flavonoids Mitogen-Activated Protein Kinase 3 Calpain Uncoupling Agents Calcium-Binding Proteins Dipeptides medicine.disease Coronary Vessels Cell biology Mitochondria Rats B vitamins Oxidative Stress chemistry Matrix Metalloproteinase 9 biology.protein Endothelium Vascular Signal transduction Cardiology and Cardiovascular Medicine |
| Zdroj: | American journal of physiology. Heart and circulatory physiology. 291(6) |
| ISSN: | 0363-6135 |
| Popis: | Hyperhomocysteinemia (HHcy) is associated with atherosclerosis, stroke, and dementia. Hcy causes extracellular matrix remodeling by the activation of matrix metalloproteinase-9 (MMP-9), in part, by inducing redox signaling and modulating the intracellular calcium dynamics. Calpains are the calcium-dependent cysteine proteases that are implicated in mitochondrial damage via oxidative burst. Mitochondrial abnormalities have been identified in HHcy. The mechanism of Hcy-induced extracellular matrix remodeling by MMP-9 activation via mitochondrial pathway is largely unknown. We report a novel role of calpains in mitochondrial-mediated MMP-9 activation by Hcy in cultured rat heart microvascular endothelial cells. Our observations suggested that calpain regulates Hcy-induced MMP-9 expression and activity. We showed that Hcy activates calpain-1, but not calpain-2, in a calcium-dependent manner. Interestingly, the enhanced calpain activity was not mirrored by the decreased levels of its endogenous inhibitor calpastatin. We presented evidence that Hcy induces the translocation of active calpain from cytosol to mitochondria, leading to MMP-9 activation, in part, by causing intramitochondrial oxidative burst. Furthermore, studies with pharmacological inhibitors of calpain (calpeptin and calpain-1 inhibitor), ERK (PD-98059) and the mitochondrial uncoupler FCCP suggested that calpain and ERK-1/2 are the major events within the Hcy/MMP-9 signal axis and that intramitochondrial oxidative stress regulates MMP-9 via ERK-1/2 signal cascade. Taken together, these findings determine the novel role of mitochondrial translocation of calpain-1 in MMP-9 activation during HHcy, in part, by increasing mitochondrial oxidative tress. |
| Databáze: | OpenAIRE |
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