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Published on: November 29, 2018
Alterations in dystrophin-related glycoproteins in development of right ventricular failure in rats
Takuya Daicho1, Yoriko Daisho, Suguru Kojima
1Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, Japan.
Abstract:
Genetic depletion of the dystrophin-related glycoprotein (DRGP) complex causes cardiomyopathy in animals and humans. The present study was undertaken to explore the possible involvement of alterations in DRGP in the development of the right ventricular failure in monocrotaline-administered rats (MCT rats). At the 6th and 8th weeks after subcutaneous administration of 60 mg/kg monocrotaline, echocardiographic examination showed that cardiac output indices were decreased and that the right ventricular Tei indices were increased, suggesting that right ventricular failure occurs, at the latest, by 6 weeks after monocrotaline-administration. The levels of alpha- and beta-sarcoglycan and beta-dystroglycan in the right ventricle of the MCT rats at the 6th and 8th weeks were markedly decreased, and these decreases were inversely related to the increase in the right ventricular Tei index of the MCT-administered animals. The content and activity of the Ca(2+)-activated neutral protease m-calpain in the right ventricle of the MCT rats were increased at the 4th to 8th weeks and those of matrix metalloproteinase-2, at the 6th and 8th weeks. These results suggest that m-calpain- and/or matrix metalloproteinase-2-mediated alterations in the contents of alpha-sarcoglycan, beta-sarcoglycan, and beta-dystroglycan may be involved in the development of right ventricular failure in MCT rats.
Insights
Genetic depletion of the dystrophin-related glycoprotein complex contributes to heart failure. This study found that alterations in this complex are linked to right ventricular failure in monocrotaline-induced rat cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Animal Models of Disease
Background:
- Genetic defects in the dystrophin-related glycoprotein (DRGP) complex are known to cause cardiomyopathy.
- The role of DRGP alterations in right ventricular failure, particularly in models of pulmonary hypertension, requires further investigation.
Purpose of the Study:
- To investigate the involvement of DRGP alterations in the development of right ventricular failure in monocrotaline-administered (MCT) rats.
- To explore the potential mechanisms, including protease activity, underlying these DRGP changes.
Main Methods:
- Rats were administered monocrotaline (60 mg/kg) subcutaneously.
- Echocardiography was performed at 6 and 8 weeks to assess cardiac function.
- Levels of alpha-sarcoglycan, beta-sarcoglycan, and beta-dystroglycan were measured in right ventricular tissue.
- Activity and content of m-calpain and matrix metalloproteinase-2 were assessed in MCT rat right ventricles.
Main Results:
- MCT rats exhibited decreased cardiac output indices and increased right ventricular Tei indices by 6 weeks, indicating right ventricular failure.
- Significant decreases in alpha-sarcoglycan, beta-sarcoglycan, and beta-dystroglycan were observed in the right ventricles of MCT rats.
- These DRGP component decreases were inversely correlated with the elevated right ventricular Tei index.
- Increased content and activity of m-calpain and matrix metalloproteinase-2 were detected in the right ventricles of MCT rats.
Conclusions:
- Alterations in the dystrophin-related glycoprotein complex are implicated in the pathogenesis of right ventricular failure in MCT rats.
- Increased activity of m-calpain and/or matrix metalloproteinase-2 may mediate the degradation of DRGP components, contributing to right ventricular dysfunction.
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