title: Farnesyl pyrophosphate synthase inhibitor, ibandronate, improves endothelial function in spontaneously hypertensive rats.
abstract: Reactive oxygen species (ROS), originating predominantly from vascular smooth muscle cells (VSMCs), lead to vascular damage and endothelial dysfunction in rats with hypertension. The downstream signaling pathways of farnesyl pyrophosphate (FPP) synthase, Ras-related C3 botulinum toxin substrate 1 (Rac1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, mediate the generation of ROS. The present study investigated the effect of the FPP synthase inhibitor, ibandronate, on ROS production, the possible beneficial effect on endothelial dysfunction and the underlying mechanisms in spontaneously hypertensive rats (SHRs). The SHRs were treated with ibandronate for 30 days. Endothelium‑dependent and independent vasorelaxation were measured in isolated aortic rings. Additionally, VSMCs from the SHRs and Wistar‑Kyoto (WKY) rats were cultured. The production of ROS and activation of NADPH oxidase were determined using fluorescence and chemiluminescence, respectively, in vivo and in vitro. Angiotensin II (Ang II) increased ROS production in the cultured VSMCs from the WKY rats and SHRs, in a concentration‑dependent manner. The Ang II‑induced responses were more marked in the SHR VSMCs, compare with those in the WKY VSMCs, however, the response decreased significantly following ibandronate pretreatment. Treatment with ibandronate significantly decreased the production of ROS, translocation of NADPH oxidase subunit p47phox, and activities of NADPH oxidase and Rac1 in the aorta and VSMCs, and improved the impaired endothelium‑dependent vasodilation in the SHRs. Adding geranylgeraniol, but not farnesol or mevalonate, reversed the inhibitory effects of ibandronate. In addition, inhibiting geranylgeranyl-transferase mimicked the effect of ibandronate on the excess oxidative response. Ibandronate exerted cellular antioxidant effects through the Rac1/NADPH oxidase pathway. These effects may have contributed to the vasoprotective effects on the impaired endothelium in SHRs.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Cardiology, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China.
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Du
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Shen-Jiang
authors.initials: SJ
authors.lastname: Hu
mesh_terms: D000818:Animals; D004164:Diphosphonates / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000077557:Ibandronic Acid; D019255:NADPH Oxidases / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004164:Diphosphonates; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D051228:Geranyltranstransferase; D000077557:Ibandronic Acid