Enhanced isradipine sensitivity in vascular smooth muscle cells due to hypoxia-induced Ca v 1.2 splicing and RbFox1/Fox2 downregulation.

Autor: Poore CP; Calcium Signaling Laboratory, National Neuroscience Institute, Singapore City, Singapore., Yang J; School of Public Health, Guangxi Medical University, Nanning, China., Wei S; Calcium Signaling Laboratory, National Neuroscience Institute, Singapore City, Singapore., Fhu CK; Calcium Signaling Laboratory, National Neuroscience Institute, Singapore City, Singapore., Bichler Z; Neurobehavioural Phenotyping Core, Center for Biometric Analysis, The Jackson Laboratory, Bar Harbor, ME, USA., Wang J; Department of Physiology, Nanjing Medical University, Nanjing, China., Soong TW; Department of Physiology, National University of Singapore, Singapore, Singapore., Liao P; Calcium Signaling Laboratory, National Neuroscience Institute, Singapore City, Singapore.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2024 Oct; Vol. 291 (19), pp. 4265-4285. Date of Electronic Publication: 2024 May 24.
DOI: 10.1111/febs.17159
Abstrakt: Calcium influx via the L-type voltage-gated Ca v 1.2 calcium channel in smooth muscle cells regulates vascular contraction. Calcium channel blockers (CCBs) are widely used to treat hypertension by inhibiting Ca v 1.2 channels. Using the vascular smooth muscle cell line, A7r5 and primary culture of cerebral vascular smooth muscle cells, we found that the expression and function of Ca v 1.2 channels are downregulated during hypoxia. Furthermore, hypoxia induces structural changes in Ca v 1.2 channels via alternative splicing. The expression of exon 9* is upregulated, whereas exon 33 is downregulated. Such structural alterations of Ca v 1.2 channels are caused by the decreased expression of RNA-binding proteins RNA-binding protein fox-1 homolog 1 and 2 (RbFox1 and RbFox2). Overexpression of RbFox1 and RbFox2 prevents hypoxia-induced exon 9* inclusion and exon 33 exclusion. Importantly, such structural alterations of the Ca v 1.2 channel partly contribute to the enhanced sensitivity of Ca v 1.2 to isradipine (a CCB) under hypoxia. Overexpression of RbFox1 and RbFox2 successfully reduces isradipine sensitivity in hypoxic smooth muscle cells. Our results suggest a new strategy to manage ischemic diseases such as stroke and myocardial infarction.
(© 2024 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
Externí odkaz: