TY - JOUR
T1 - Artherosclerosis-related molecular alteration of the human Ca V1.2 calcium channel α1C subunit
AU - Tiwari, Swasti
AU - Zhang, Yuwei
AU - Heller, Jennifer
AU - Abernethy, Darrell R.
AU - Soldatov, Nikolai M.
PY - 2006/11/7
Y1 - 2006/11/7
N2 - 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.
AB - 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.
KW - Alternative splicing
KW - Cell proliferation
KW - Vascular smooth muscle cells
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U2 - 10.1073/pnas.0606539103
DO - 10.1073/pnas.0606539103
M3 - Article
C2 - 17071743
AN - SCOPUS:33750957976
SN - 0027-8424
VL - 103
SP - 17024
EP - 17029
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -