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Implications of protease activation in cardiac dysfunction and development of genetic cardiomyopathy in hamsters
Alison L Müller1, Darren Freed, Larry Hryshko
1Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada.
Insights
Protease activity contributes to heart dysfunction in various heart diseases. Increased protease activity in genetic cardiomyopathy models suggests a key role in subcellular remodeling and cardiac dysfunction.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Protease Biochemistry
Background:
- Protein degradation by proteases contributes to cardiovascular dysfunction in heart diseases.
- Altered proteolytic activities are observed in various forms of heart failure, including hypertrophic, dilated, hypertensive, diabetic, and ischemic cardiomyopathy.
- Genetic cardiomyopathy models, such as those in hamsters, are valuable for studying heart failure mechanisms.
Purpose of the Study:
- To investigate the role of proteases in subcellular remodeling and cardiac dysfunction in genetic cardiomyopathy.
- To explore the link between increased protease activity and organelle/extracellular matrix alterations in failing hearts.
Main Methods:
- Utilized genetic cardiomyopathy hamster models to study heart failure.
- Analyzed alterations in myocardial organelles (sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria) and extracellular matrix.
- Assessed the activities of specific proteases, including calpains and matrix metalloproteinases.
Main Results:
- Observed significant alterations in myocardial organelle function and extracellular matrix in failing hearts of cardiomyopathic hamsters.
- Found increased activities of calpains and matrix metalloproteinases in the hearts of these hamsters.
- These changes were linked to altered gene expression and protein content, indicative of subcellular remodeling.
Conclusions:
- Increased protease activation is a significant factor in subcellular remodeling and cardiac dysfunction in genetic cardiomyopathy.
- Proteolytic enzymes play a crucial role in the pathogenesis of heart failure associated with genetic cardiomyopathies.
- Targeting protease activity may offer therapeutic strategies for genetic cardiomyopathies.
Abstract:
It has become evident that protein degradation by proteolytic enzymes, known as proteases, is partly responsible for cardiovascular dysfunction in various types of heart disease. Both extracellular and intracellular alterations in proteolytic activities are invariably seen in heart failure associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, hypertensive cardiomyopathy, diabetic cardiomyopathy, and ischemic cardiomyopathy. Genetic cardiomyopathy displayed in different strains of hamsters provides a useful model for studying heart failure due to either cardiac hypertrophy or cardiac dilation. Alterations in the function of several myocardial organelles such as sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, as well as extracellular matrix have been shown to be due to subcellular remodeling as a consequence of changes in gene expression and protein content in failing hearts from cardiomyopathic hamsters. In view of the increased activities of various proteases, including calpains and matrix metalloproteinases in the hearts of genetically determined hamsters, it is proposed that the activation of different proteases may also represent an important determinant of subcellular remodeling and cardiac dysfunction associated with genetic cardiomyopathy.
