title: Augmented Ca2+ influx is involved in the mechanism of enhanced proliferation of cultured vascular smooth muscle cells from spontaneously diabetic Goto-Kakizaki rats.
abstract: To investigate whether augmented calcium influx is involved in the mechanism of the enhanced proliferation of vascular smooth muscle cells (VSMCs) in diabetes, we studied the association between proliferation and cytosolic free calcium concentration ([Ca2+]i) in cultured aortic VSMCs from spontaneously diabetic Goto-Kakizaki (GK) and Wistar rats. Serum, angiotensin II and Bay K 8644, a voltage-dependent Ca2+ channel (VDC) agonist, stimulated the proliferation of VSMCs; the magnitude was greater in VSMCs from GK than Wistar rats. VDC blockers, verapamil and nicardipine, inhibited Bay K 8644-induced cell proliferation, and the difference in the proliferation of VSMCs between GK and Wistar rats disappeared. Angiotensin II-induced proliferation was only partially inhibited by VDC blockers, and enhanced proliferation of GK-VSMCs was still observed. Bay K 8644 and angiotensin II increased [Ca2+]i, and the increase was augmented in GK-VSMCs. Bay K 8644-induced [Ca2+]i increase was completely inhibited by pretreatment with verapamil or removal of extracellular Ca2+, suggesting that VDC is associated with this increase. Although angiotensin II-induced [Ca2+]i increase was not affected by verapamil, removal of extracellular Ca2+ slightly but significantly attenuated angiotensin II-induced [Ca2+]i increase, suggesting that VDC blocker-insensitive receptor-activated Ca2+ influx is involved. These results indicate that augmented Ca2+ influx via VDC and a receptor-activated pathway may be involved in the mechanism of the enhanced proliferation of VSMCs from GK rats.
authors.affiliation: Department of Geriatrics, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Japan.
authors.forename: H J
authors.initials: HJ
authors.lastname: Yoo
authors.forename: K
authors.initials: K
authors.lastname: Kozaki
authors.forename: M
authors.initials: M
authors.lastname: Akishita
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: M
authors.initials: M
authors.lastname: Eto
authors.forename: K
authors.initials: K
authors.lastname: Nagano
authors.forename: N
authors.initials: N
authors.lastname: Sudo
authors.forename: M
authors.initials: M
authors.lastname: Hashimoto
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: M
authors.initials: M
authors.lastname: Yoshizumi
authors.forename: K
authors.initials: K
authors.lastname: Toba
authors.forename: Y
authors.initials: Y
authors.lastname: Ouchi
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology*; D007328:Insulin / Q000097:blood; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009529:Nicardipine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007328:Insulin; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D009529:Nicardipine; D002118:Calcium