title: Des-aspartate-angiotensin I causes specific release of PGE2 and PGI2 in HUVEC via the angiotensin AT1 receptor and biased agonism.
abstract: DAA-I (des-aspartate-angiotensin I), an endogenous angiotensin, had been shown earlier to ameliorate animal models of cardiovascular diseases via the angiotensin AT1 receptor and prostaglandins. The present study investigated further the action of DAA-I on the release of PGE2, PGI2, PGF2α and TXA2 in HUVEC. 10(-11)-10(-8)M DAA-I and 15min incubation specifically released PGE2 and PGI2. The release was inhibited by losartan and indomethacin but not by PD123319 and NS398 indicating that the angiotensin AT1 receptor and COX-1 mediate the release. At concentrations higher than 10(-7)M, DAA-I mimics the action of angiotensin II by releasing TXA2 but had no effect on the production of PGF2α. At similar concentrations and 4h incubation, DAA-I increased the release of the 4 prostaglandins via the angiotensin AT1 receptor and COX-2, again mimicking the action of angiotensin II. HUVEC that were preincubated with DAA-I or angiotensin II, released similar profiles of prostaglandins when incubated with arachidonic acid after the angiotensin had been washed off. We postulate that the internalized DAA-I/receptor complex remains active and mediates the conversion of arachidonic acid to the respective prostaglandins. The release of PGE2 and PGI2 via the angiotensin AT1 receptor and COX-1 is a novel specific action of DAA-I and is likely responsible for its beneficial effects seen in earlier studies. This specific action is definable as a biased agonism of the angiotensin AT1 receptor, which identifies DAA-I as a novel biased agonist and potential therapeutic that is able to produce specific prostaglandins at nanomolar concentrations.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wen
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore.
authors.forename: Kok-Onn
authors.initials: KO
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: Sai-Zhen
authors.initials: SZ
authors.lastname: Sim
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors.forename: Xiao-Guang
authors.initials: XG
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore. Electronic address: phcsimmk@nus.edu.sg.
authors.forename: Meng-Kwoon
authors.initials: MK
authors.lastname: Sim
mesh_terms: D000803:Angiotensin I / Q000031:analogs & derivatives* / Q000494:pharmacology; D016718:Arachidonic Acid / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists* / Q000378:metabolism*; D013997:Time Factors
chemical_list: D044140:Receptor, Angiotensin, Type 1; C529402:des-aspartate-angiotensin I; D016718:Arachidonic Acid; D000803:Angiotensin I; D011464:Epoprostenol; D015232:Dinoprostone
keywords: Des-aspartate-angiotensin I; HUVEC; Losartan; PGE2; PGI2; Prostaglandins