In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 45 ( 2006-11-07), p. 17024-17029
Abstract:
Atherosclerosis is an inflammatory process characterized by proliferation and dedifferentiation of vascular smooth muscle cells (VSMC). Ca v 1.2 calcium channels may have a role in atherosclerosis because they are essential for Ca 2+ -signal transduction in VSMC. The pore-forming Ca v 1.2α1 subunit of the channel is subject to alternative splicing. Here, we investigated whether the Ca v 1.2α1 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 Ca v 1.2α1 transcripts characterized by the presence of exons 21 and 41A. In VSMC affected by atherosclerosis, expression of the Ca v 1.2α1 transcript was reduced and the Ca v 1.2α1 splice variants were replaced with the unique exon-22 isoform lacking exon 41A. Molecular remodeling of the Ca v 1.2α1 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 Ca 2+ 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 Ca v 1.2α1 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 Ca v 1.2α1 gene in the human artery that causes molecular and electrophysiological remodeling of Ca v 1.2 calcium channels and possibly affects VSMC proliferation.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0606539103
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2006
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
Permalink
