Azelnidipine, a dihydropyridine-based calcium antagonist, inhibits angiotensin II-induced oxidative stress generation and downregulation of pigment epithelium-derived factor mRNA levels in microvascular endothelial cells.
We have previously shown that azelnidipine, a long-acting dihydropyridine-based calcium antagonist (DHP), inhibited tumor necrosis factor-alpha-induced endothelial cell (EC) activation through its antioxidative properties. However whether azelnidipine could also block the angiotensin II (Ang II)-signaling in ECs remains to be elucidated. Since Ang II-type 1 receptor interaction could contribute to exacerbation of diabetic retinopathy by downregulating pigment epithelium-derived factor (PEDF) gene expression in ECs, we examined here whether azelnidipine inhibited the Ang II-induced reactive oxygen species (ROS) generation and subsequent PEDF gene suppression in microvascular ECs. Azelnidipine, but not nitrendipine, the other popular DHFP completely inhibited the Ang II-induced ROS generation in ECs. Furthermore, azelnidipine, but not nitrendipine, was found to partially restore decreased PEDF mRNA levels in Ang II-exposed ECs. The present study suggests that azelnidipine could inhibit the Ang II-induced decrease in PEDF mRNA levels in ECs through its antioxidative properties. Upregulation of PEDF by azelnidipine may become a therapeutic target for the treatment of diabetic retinopathy associated with hypertension.
Matsui
T
T
Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Yamagishi
S
S
Nakamura
K
K
Kikuchi
S
S
Inoue
H
H
D000804:Angiotensin II / Q000378:metabolism*; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism*; D005136:Eye Proteins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008833:Microcirculation / Q000166:cytology; D009414:Nerve Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D009568:Nitrendipine / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015843:Serpins / Q000096:biosynthesis* / Q000235:genetics; D000099174:Pigment Epithelium-Derived Factor
D000804:Angiotensin II; D001383:Azetidinecarboxylic Acid; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D005136:Eye Proteins; D009414:Nerve Growth Factors; D009568:Nitrendipine; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C061679:azelnidipine