JCK-9
Blockade of T-type calcium channels attenuates smooth muscle cell migration, neointimal formation, and oxygen-induced vascular contraction in rat ductus arteriosus
Cardiovascular Research Institute,1) Department of Pediatrics,2) Yokohama City University Graduate School of Medicine, Kanagawa, Japan, Cardiovascular Research Institute, Departments of Cell Biology and Molecular Medicine and Medicine (Cardiology), New Jersey Medical School, NJ, U.S.A.,3) Department of Life Science and Medical Bio-science, Waseda University, Tokyo, Japan4)
Toru Akaike,1) Utako Yokoyama,1) Mei Hua Jin,1) Qibin Jiao,1) Mari Iwamoto,2) Yoshihiro Ishikawa,1, 3) Susumu Minamisawa1, 4)
Ca2+ influx through voltage-dependent Ca2+ channels regulates vascular remodeling and contraction. However, the role of T-type Ca2+ channels (TCCs) has remained unknown in the ductus arteriosus (DA). Here we hypothesized that Ca2+ influx via TCC contributed to DA closure through promoting neointimal cushion formation and oxygen-induced vascular contraction. Quantitative RT-PCR analysis revealed that αG, a TCC subtype, was significantly up-regulated in rat neonatal DA tissues at birth and in DA smooth muscle cells (SMCs) that were exposed to oxygen. The expression of αG mRNA was higher in DA than in the aorta. Immunohistlogical analysis revealed that αG was localized predominantly to the region of intimal thickening in fetal DA at term and to the central core of neonatal DA at birth. To examine the effects of TCCs, we used αG over-expression, αG-specific siRNA, and R(‐)-efonidipine, a highly selective TCC blocker that was recently developed. αG-specific siRNAs inhibited SMC migration by 58% relative to negative siRNA (n = 6, p < 0.01). R(‐)-efonidipine suppressed SMC migration by 52% in a dose-dependent manner (n = 5, p < 0.01). SMC migration was increased by 1.6 fold when αG plasmid was over-expressed (n = 7, p < 0.01). We examined the effects of R(‐)-efonidipine on oxygen-induced vascular contraction using a vascular ring of fetal DA at term. R(‐)-efonidipine attenuated oxygen-induced vascular contraction in a dose-dependent manner. Isometric tension induced by oxygen was decreased by 60% in the presence of 10-5M of R(‐)-efonidipine (n = 18, p < 0.01). Finally, we examine the effects of R(‐)-efonidipine on the closures of the in vivo DA in neonatal rats. R(‐)-efonidipine significantly delayed the closure of the in vivo DA (n = 7). In conclusion, TCC, especially αG, blockade attenuated SMC migration, neointimal formation, and oxygen-induced vascular contraction in rat DA. The present study implies that TCC blockade is an alternative therapeutic strategy to keep DA open for patients with DA-dependent congenital heart defects.

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