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CBL aggravates Ang II-induced cardiac hypertrophy via the VHL/HIF-1α pathway
Yuting Yang1, Pengtao Zou1, Lin He1
1Nanchang University, Nanchang, Jiangxi, 330006, China; Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
Insights
Casitas B cell lymphoma (CBL) protein ligase exacerbates cardiac hypertrophy by activating HIF-1α. Inhibiting CBL or HIF-1α may offer new treatments for hypertrophic cardiomyopathy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiology
Background:
- Casitas B cell lymphoma (CBL) is a ubiquitin protein ligase involved in cellular protein regulation.
- The specific role of CBL in cardiac hypertrophy remains largely uncharacterized.
- Cardiac hypertrophy is a significant risk factor for heart failure.
Purpose of the Study:
- To investigate the role of CBL in cardiac hypertrophy.
- To elucidate the molecular mechanisms underlying CBL's function in the hypertrophic heart.
- To explore potential therapeutic targets for hypertrophic cardiomyopathy.
Main Methods:
- Utilized an Angiotensin II (Ang II)-induced mouse model of cardiac hypertrophy.
- Employed Ang II-treated H9C2 cells for in vitro studies.
- Investigated CBL and HIF-1α expression and interaction using molecular biology techniques.
- Assessed the impact of CBL and HIF-1α manipulation on hypertrophic markers.
Main Results:
- CBL expression was upregulated in both the animal model and cell culture under Ang II stimulation.
- Interference with CBL expression reduced myocardial hypertrophy and related gene expression.
- CBL was found to activate HIF-1α, a known factor in hypertrophy.
- CBL directly interacted with and degraded VHL (von Hippel-Lindau tumor suppressor), increasing HIF-1α activity.
- Blocking HIF-1α reversed the hypertrophic effects induced by CBL.
Conclusions:
- CBL plays a significant role in promoting cardiac hypertrophy.
- The CBL/HIF-1α signaling axis is a key pathway in the development of cardiac hypertrophy.
- Targeting the CBL/HIF-1α axis presents a potential therapeutic strategy for hypertrophic cardiomyopathy.
Abstract:
CBL (Casitas B cell lymphoma), an important ubiquitin protein ligase, is involved in protein folding, protein maturation, and proteasome-dependent protein catabolism in different cells. However, its role in cardiac hypertrophy is still unclear. In this study, we found that expression of CBL is increased in an Ang II-induced mouse cardiac hypertrophy animal model and in Ang II-treated H9C2 cells. Interference with CBL expression attenuates the degree of myocardial hypertrophy as well as the expression of hypertrophy-related genes in H9C2 cells. Further research found that CBL aggravates myocardial hypertrophy by activating HIF-1α, which is an aggravating factor for hypertrophy. The effect of CBL on promoting myocardial hypertrophy was reversed by interference with HIF-1α. Mechanistically, we found that CBL directly interacted with and degraded VHL by increasing its ubiquitination level, which is a widely accepted regulatory factor of HIF-1α. Finally, our results showed that CBL was partially dependent on degradation of VHL and that activation of HIF-1α promoted myocardial hypertrophy. Collectively, these findings suggest that strategies based on activation of the CBL/HIF-1α axis might be promising for the treatment of hypertrophic cardiomyopathy.
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