Document Type
Article
Publication Date
10-1-2024
Original Citation
Poore C,
Yang J,
Wei S,
Fhu C,
Bichler Z,
Wang J,
Soong T,
Liao P.
Enhanced isradipine sensitivity in vascular smooth muscle cells due to hypoxia-induced Ca FEBS J. 2024;291(19):4265-85.
Keywords
JMG, Calcium Channels, L-Type, Muscle, Smooth, Vascular, RNA Splicing Factors, Animals, Myocytes, Smooth Muscle, Alternative Splicing, Down-Regulation, Rats, Cell Hypoxia, Exons, Mice, Calcium Channel Blockers, RNA-Binding Proteins
JAX Source
FEBS J. 2024;291(19):4265-85.
ISSN
1742-4658
PMID
38794806
DOI
https://doi.org/10.1111/febs.17159
Abstract
Calcium influx via the L-type voltage-gated Cav 1.2 calcium channel in
smooth muscle cells regulates vascular contraction. Calcium channel
blockers (CCBs) are widely used to treat hypertension by inhibiting Cav 1.2
channels. Using the vascular smooth muscle cell line, A7r5 and primary cul-
ture of cerebral vascular smooth muscle cells, we found that the expression
and function of Cav 1.2 channels are downregulated during hypoxia. Further-
more, hypoxia induces structural changes in Cav1.2 channels via alternative
splicing. The expression of exon 9* is upregulated, whereas exon 33 is down-
regulated. Such structural alterations of Cav1.2 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 Cav 1.2 channel partly contrib-
ute to the enhanced sensitivity of Ca v1.2 to isradipine (a CCB) under hyp-
oxia. 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.
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