title: eNOS-dependent antisenscence effect of a calcium channel blocker in human endothelial cells.
abstract: Senescence of vascular endothelial cells is an important contributor to the pathogenesis of age-associated vascular disorders such as atherosclerosis. We investigated the effects of antihypertensive agents on high glucose-induced cellular senescence in human umbilical venous endothelial cells (HUVECs). Exposure of HUVECs to high glucose (22 mM) for 3 days increased senescence-associated- β-galactosidase (SA-β-gal) activity, a senescence marker, and decreased telomerase activity, a replicative senescence marker. The calcium channel blocker nifedipine, but not the β1-adrenergic blocking agent atenolol or the angiotensin-converting enzyme inhibitor perindopril, reduced SA-β-gal positive cells and prevented a decrease in telomerase activity in a high-glucose environment. This beneficial effect of nifedipine was associated with reduced reactive oxygen species (ROS) and increased endothelial nitric oxide synthase (eNOS) activity. Thus, nifedipine prevented high glucose-induced ROS generation and increased basal eNOS phosphorylation level at Ser-1177. Treatment with N (G)-nitro-L-arginine (L-NAME) and transfection of small interfering RNA (siRNA) targeting eNOS eliminated the anti-senscence effect of nifedipine. These results demonstrate that nifedipine can prevent endothelial cell senescence in an eNOS-dependent manner. The anti-senescence action of nifedipine may represent a novel mechanism by which it protects against atherosclerosis.
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Toshio
authors: T
authors: Hayashi
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Tomoe
authors: T
authors: Yamaguchi
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Yasufumi
authors: Y
authors: Sakakibara
authors: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
authors: Kumiko
authors: K
authors: Taguchi
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Morihiko
authors: M
authors: Maeda
authors: Department of Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Masafumi
authors: M
authors: Kuzuya
authors: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
authors: Yuichi
authors: Y
authors: Hattori
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D001262:Atenolol / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016922:Cellular Senescence / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D020913:Perindopril / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D000804:Angiotensin II; D001262:Atenolol; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D001616:beta-Galactosidase; D009543:Nifedipine; D005947:Glucose; D020913:Perindopril