Atherosclerosis-related molecular alteration of the human CaV1.2 calcium channel alpha1C subunit.
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)1.2alpha1 subunit of the channel is subject to alternative splicing. Here, we investigated whether the Ca(v)1.2alpha1 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)1.2alpha1 transcripts characterized by the presence of exons 21 and 41A. In VSMC affected by atherosclerosis, expression of the Ca(v)1.2alpha1 transcript was reduced and the Ca(v)1.2alpha1 splice variants were replaced with the unique exon-22 isoform lacking exon 41A. Molecular remodeling of the Ca(v)1.2alpha1 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)1.2alpha1 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)1.2alpha1 gene in the human artery that causes molecular and electrophysiological remodeling of Ca(v)1.2 calcium channels and possibly affects VSMC proliferation.
Tiwari
Swasti
S
National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Zhang
Yuwei
Y
Heller
Jennifer
J
Abernethy
Darrell R
DR
Soldatov
Nikolai M
NM
D000368:Aged; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D017931:DNA Primers / Q000235:genetics; D005091:Exons; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D020746:Calcium Channels, L-Type; D017931:DNA Primers; C419385:L-type calcium channel alpha(1C); D012333:RNA, Messenger