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Diminished Rbfox1 increases vascular constriction by dynamically regulating alternative splicing of CaV1.2 calcium
Miaomiao Song1, Wei Hou1, Atta Ul Mustafa1
1Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
Abstract:
Calcium influx from depolarized CaV1.2 calcium channels triggers the contraction of vascular smooth muscle cells (VSMCs), which is important for maintaining vascular myogenic tone and blood pressure. The function of CaV1.2 channel can be subtly modulated by alternative splicing (AS), and its aberrant splicing involves in the pathogenesis of multiple cardiovascular diseases. The RNA-binding protein Rbfox1 is reported to regulate the AS events of CaV1.2 channel in the neuronal development, but its potential roles in vascular CaV1.2 channels and vasoconstriction remain undefined. Here, we detect Rbfox1 is expressed in rat vascular smooth muscles. Moreover, the protein level of Rbfox1 is dramatically decreased in the hypertensive small arteries from spontaneously hypertensive rats in comparison with normotensive ones from Wistar-Kyoto rats. In VSMCs, Rbfox1 could dynamically regulate the AS of CaV1.2 exons 9* and 33. By whole-cell patch clamp, we identify knockdown of Rbfox1 induces the hyperpolarization of CaV1.2 current-voltage relationship curve in VSMCs. Furthermore, siRNA-mediated knockdown of Rbfox1 increases the K+-induced constriction of rat mesenteric arteries. In summary, our results indicate Rbfox1 modulates vascular constriction by dynamically regulating CaV1.2 alternative exons 9* and 33. Therefore, our work elucidates the underlying mechanisms for CaV1.2 channels regulation and provides a potential therapeutic target for hypertension.
Insights
The RNA-binding protein Rbfox1 regulates vascular smooth muscle cell contraction by controlling CaV1.2 channel alternative splicing. Reduced Rbfox1 levels in hypertension impair this regulation, impacting blood pressure.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- RNA Biology
Background:
- Vascular smooth muscle cell (VSMC) contraction, mediated by CaV1.2 calcium channels, is crucial for blood pressure regulation.
- Alternative splicing (AS) of CaV1.2 channels affects their function and is implicated in cardiovascular diseases.
- The role of RNA-binding protein Rbfox1 in vascular CaV1.2 AS and VSMC function is unknown.
Purpose of the Study:
- To investigate the expression and function of Rbfox1 in rat vascular smooth muscle.
- To determine if Rbfox1 regulates CaV1.2 alternative splicing in VSMCs.
- To assess the impact of Rbfox1 on vascular constriction and CaV1.2 channel activity.
Main Methods:
- Rbfox1 expression analysis in rat vascular smooth muscle and hypertensive models.
- RNA-binding protein immunoprecipitation and RT-PCR to assess CaV1.2 AS.
- Whole-cell patch clamp electrophysiology to measure CaV1.2 channel currents.
- siRNA-mediated knockdown of Rbfox1 in VSMCs and mesenteric artery constriction assays.
Main Results:
- Rbfox1 is expressed in rat VSMCs and its levels are decreased in hypertensive rats.
- Rbfox1 dynamically regulates alternative splicing of CaV1.2 exons 9* and 33 in VSMCs.
- Rbfox1 knockdown leads to hyperpolarization of the CaV1.2 current-voltage relationship.
- Rbfox1 knockdown increases potassium-induced vasoconstriction in rat mesenteric arteries.
Conclusions:
- Rbfox1 modulates vascular smooth muscle contraction by regulating CaV1.2 alternative splicing.
- Decreased Rbfox1 contributes to hypertension by altering CaV1.2 channel function.
- Rbfox1 represents a potential therapeutic target for hypertension.
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