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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Caveolin-1/3 double-knockout mice are viable, but lack both muscle and non-muscle caveolae, and develop a severe
David S Park1, Scott E Woodman, William Schubert
1Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Abstract:
The caveolin gene family consists of caveolins 1, 2, and 3. Caveolins 1 and 2 are co-expressed in many cell types, such as endothelial cells, fibroblasts, smooth muscle cells and adipocytes, where they form a heteroligomeric complex. In contrast, the expression of caveolin-3 is muscle-specific. Thus, the expression of caveolin-1 is required for caveolae formation in non-muscle cells, while the expression of caveolin-3 drives caveolae formation in striated muscle cell types (cardiac and skeletal). To create a truly caveolae-deficient mouse, we interbred Cav-1 null mice and Cav-3 null mice to generate Cav-1/Cav-3 double-knockout (Cav-1/3 dKO) mice. Here, we report that Cav-1/3 dKO mice are viable and fertile, despite the fact that they lack morphologically identifiable caveolae in endothelia, adipocytes, smooth muscle cells, skeletal muscle fibers, and cardiac myocytes. We also show that these mice are deficient in all three caveolin gene products, as caveolin-2 is unstable in the absence of caveolin-1. Interestingly, Cav-1/3 dKO mice develop a severe cardiomyopathy. At 2 months of age, analysis of Cav-1/3 dKO hearts via gated magnetic resonance imaging reveals a dramatic increase in left ventricular wall thickness, as compared with Cav-1-KO, Cav-3 KO, and wild-type mice. Further functional analysis of Cav-1/3 dKO hearts via transthoracic echocardiography demonstrates hypertrophy and dilation of the left ventricle, with a significant decrease in fractional shortening. As predicted, Northern analysis of RNA derived from the left ventricle of Cav-1/3 dKO mice shows a dramatic up-regulation of the atrial natriuretic factor message, a well-established biochemical marker of cardiac hypertrophy. Finally, histological analysis of Cav-1/3 dKO hearts reveals hypertrophy, disorganization, and degeneration of the cardiac myocytes, as well as chronic interstitial fibrosis and inflammation. Thus, dual ablation of both Cav-1 and Cav-3 genes in mice leads to a pleiotropic defect in caveolae formation and severe cardiomyopathy.
Insights
Mice lacking both caveolin-1 and caveolin-3 (Cav-1/3 dKO) are viable but develop severe cardiomyopathy. This study reveals dual gene ablation disrupts caveolae formation and leads to significant cardiac defects in these mice.
Area of Science:
- Cell Biology
- Genetics
- Cardiovascular Research
Background:
- Caveolins are essential protein components of caveolae, involved in cellular processes.
- Caveolin-1 (Cav-1) and Caveolin-3 (Cav-3) have distinct but overlapping roles in caveolae formation across different cell types.
- Cav-1 is crucial for non-muscle cells, while Cav-3 is vital for muscle cells.
Purpose of the Study:
- To investigate the in vivo consequences of complete caveolae deficiency.
- To generate and characterize mice lacking both Cav-1 and Cav-3 (Cav-1/3 dKO mice).
- To determine the impact of dual caveolin gene ablation on cardiac function and morphology.
Main Methods:
- Generation of Cav-1/Cav-3 double-knockout (Cav-1/3 dKO) mice by interbreeding Cav-1 null and Cav-3 null mice.
- Morphological assessment of caveolae absence in various tissues.
- Cardiac function analysis using gated magnetic resonance imaging (MRI) and transthoracic echocardiography.
- Biochemical analysis (Northern blot) for cardiac hypertrophy markers.
- Histological examination of cardiac tissue.
Main Results:
- Cav-1/3 dKO mice are viable and fertile, lacking morphologically identifiable caveolae in multiple cell types.
- Caveolin-2 is unstable without Cav-1, leading to a deficiency in all three caveolin gene products.
- Cav-1/3 dKO mice exhibit a severe cardiomyopathy characterized by increased left ventricular wall thickness, hypertrophy, dilation, and reduced fractional shortening.
- Biochemical and histological analyses confirm cardiac hypertrophy, myocyte disorganization, degeneration, fibrosis, and inflammation in dKO hearts.
Conclusions:
- Dual ablation of Cav-1 and Cav-3 leads to a complete and pleiotropic defect in caveolae formation.
- The absence of caveolae due to combined Cav-1 and Cav-3 deficiency results in severe cardiac pathology.
- This study highlights the critical roles of caveolins in maintaining cardiac structure and function.
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