Artherosclerosis-related molecular alteration of the human Ca V1.2 calcium channel α1C subunit

Swasti Tiwari, Yuwei Zhang, Jennifer Heller, Darrell R. Abernethy, Nikolai M. Soldatov

Research output: Contribution to journalArticlepeer-review

Abstract

Atherosclerosis is an inflammatory process characterized by proliferation and dedifferentiation of vascular smooth muscle cells (VSMC). CaV1.2 calcium channels may have a role in atherosclerosis because they are essential for Ca2+-signal transduction in VSMC. The pore-forming Ca V1.2α1 subunit of the channel is subject to alternative splicing. Here, we investigated whether the CaV1.2α1 splice variants are affected by atherosclerosis. VSMC were isolated by laser-capture microdissection from frozen sections of adjacent regions of arteries affected and not affected by atherosclerosis. In VSMC from nonatherosclerotic regions, RT-PCR analysis revealed an extended repertoire of CaV1.2α1 transcripts characterized by the presence of exons 21 and 41A. In VSMC affected by atherosclerosis, expression of the CaV1.2α1 transcript was reduced and the CaV1.2α1 splice variants were replaced with the unique exon-22 isoform lacking exon 41 A. Molecular remodeling of the Ca V1.2α1 subunits associated with atherosclerosis caused changes in electrophysiological properties of the channels, including the kinetics and voltage-dependence of inactivation, recovery from inactivation, and rundown of the Ca2+ current. Consistent with the pathophysiological state of VSMC in atherosclerosis, cell culture data pointed to a potentially important association of the exon-22 isoform of CaV1.2α1 with proliferation of VSMC. Our findings are consistent with a hypothesis that localized changes in cytokine expression generated by inflammation in atherosclerosis affect alternative splicing of the CaV1.2α1 gene in the human artery that causes molecular and electrophysiological remodeling of CaV1.2α1 calcium channels and possibly affects VSMC proliferation.

Original languageEnglish (US)
Pages (from-to)17024-17029
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number45
DOIs
StatePublished - Nov 7 2006

Keywords

  • Alternative splicing
  • Cell proliferation
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • General

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