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Published on: March 10, 2020
Upregulated Angiogenesis Is Incompetent to Rescue Dilated Cardiomyopathy Phenotype in Mice
Mohammed Arif1, Perwez Alam2, Rafeeq Ph Ahmed2
1Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Insights
This study investigated if enhancing cardiac angiogenesis could reverse dilated cardiomyopathy (DCM) in mice. Results show increased angiogenesis did not rescue the DCM phenotype, suggesting other factors are involved.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Regenerative Medicine
Background:
- Dilated cardiomyopathy (DCM) involves pathological cardiac remodeling and impaired contractility.
- Previous research suggests a link between DCM and reduced tissue angiogenesis.
- The role of enhanced angiogenesis in mitigating DCM progression remains unclear.
Purpose of the Study:
- To investigate if modulating cardiac angiogenesis can intervene in or rescue the DCM phenotype in a mouse model.
- To assess the impact of microRNA-210 (miR-210) overexpression on cardiac angiogenesis and DCM pathology.
Main Methods:
- Crossbreeding of a DCM mouse model (α-tropomyosin 54 mutant) with microRNA-210 transgenic mice (210-TG) to create TMx210 mice.
- Histopathological analysis to evaluate cardiac remodeling, including myocardial disarray, myofibrillar loss, and fibrosis.
- Assessment of angiogenic potential via blood vessel density and vascular endothelial growth factor-A (VEGF-A) expression.
- Echocardiographic evaluation of cardiac function.
Main Results:
- TMx210 and DCM mice exhibited increased heart weight to body weight ratio compared to WT and 210-TG mice.
- Histopathology confirmed pathological cardiac remodeling in both DCM and TMx210 mice.
- TMx210 and 210-TG mice showed enhanced angiogenic potential with higher blood vessel density and VEGF-A levels.
- Echocardiography revealed comparable cardiac dysfunction in DCM and TMx210 mice.
Conclusions:
- Upregulated angiogenesis mediated by miR-210 is insufficient to rescue the DCM phenotype in this mouse model.
- The findings suggest that while angiogenesis is important, it may not be the sole determinant in DCM progression or recovery.
Abstract:
Dilated cardiomyopathy (DCM) is characterized by pathologic cardiac remodeling resulting in chambers enlargement and impaired heart contractility. Previous reports and our in-silico analysis support the association of DCM phenotype and impaired tissue angiogenesis. Here, we explored whether the modulation in cardiac angiogenesis partly intervenes or rescues the DCM phenotype in mice. Here, a DCM mouse model [α-tropomyosin 54 (α-TM54) mutant] was crossbred with microRNA-210 transgenic mice (210-TG) to develop microRNA-210 (miR-210) overexpressing α-TM54 mutant mice (TMx210). Contrary to wild-type (WT) and 210-TG mice, a significant increase in heart weight to body weight ratio in aged mixed-gender TMx210 and DCM mice was recorded. Histopathological analysis revealed signs of pathological cardiac remodeling such as myocardial disarray, myofibrillar loss, and interstitial fibrosis in DCM and TMx210 mice. Contrary to WT and DCM, a significant increase in angiogenic potential was observed in TMx210 and 210-TG mice hearts which is reflected by higher blood vessel density and upregulated proangiogenic vascular endothelial growth factor-A. The echocardiographic assessment showed comparable cardiac dysfunction in DCM and TMx210 mice as compared to WT and 210-TG. Overall, the present study concludes that miR-210 mediated upregulated angiogenesis is not sufficient to rescue the DCM phenotype in mice.
