title: Arsenic causes aortic dysfunction and systemic hypertension in rats: Augmentation of angiotensin II signaling.
abstract: The groundwater pollutant arsenic can cause various cardiovascular disorders. Angiotensin II, a potent vasoconstrictor, plays an important role in vascular dysfunction by promoting changes in endothelial function, vascular reactivity, tissue remodeling and oxidative stress. We investigated whether modulation of angiotensin II signaling and redox homeostasis could be a mechanism contributing to arsenic-induced vascular disorder. Rats were exposed to arsenic at 25, 50 and 100ppm of sodium arsenite through drinking water consecutively for 90 days. Blood pressure was recorded weekly. On the 91st day, the rats were sacrificed for blood collection and isolation of thoracic aorta. Angiotensin converting enzyme and angiotensin II levels were assessed in plasma. Aortic reactivity to angiotensin II was assessed in organ-bath system. Western blot of AT1 receptors and G protein (Gαq/11), ELISA of signal transducers of MAP kinase pathway and reactive oxygen species (ROS) generation were assessed in aorta. Arsenic caused concentration-dependent increase in systolic, diastolic and mean arterial blood pressure from the 10th, 8th and 7th week onwards, respectively. Arsenic caused concentration-dependent enhancement of the angiotensin II-induced aortic contractile response. Arsenic also caused concentration-dependent increase in the plasma levels of angiotensin II and angiotensin converting enzyme and the expression of aortic AT1 receptor and Gαq/11 proteins. Arsenic increased aortic protein kinase C activity and the concentrations of protein tyrosine kinase, extracellular signal-regulated kinase-1/2 and vascular endothelial growth factor. Further, arsenic increased aortic mRNA expression of Nox2, Nox4 and p22phox, NADPH oxidase activity and ROS generation. The results suggest that arsenic-mediated enhancement of angiotensin II signaling could be an important mechanism in the arsenic-induced vascular disorder, where ROS could augment the angiotensin II signaling through activation of MAP kinase pathway.
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Prashantkumar
authors.initials: P
authors.lastname: Waghe
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Thengumpallil Sasindran
authors.initials: TS
authors.lastname: Sarath
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Kannan
authors.initials: K
authors.lastname: Kandasamy
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Soumen
authors.initials: S
authors.lastname: Choudhury
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Harikumar Sankaran
authors.initials: HS
authors.lastname: Kutty
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Mishra
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India. Electronic address: snsarkar1911@gmail.com.
authors.forename: Souvendra Nath
authors.initials: SN
authors.lastname: Sarkar
mesh_terms: D000804:Angiotensin II / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000503:physiopathology; D001151:Arsenic / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D044140:Receptor, Angiotensin, Type 1; D013481:Superoxides; D000804:Angiotensin II; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D001151:Arsenic
keywords: Angiotensin II; Arsenic; Hypertension; MAP kinase signaling; Reactive oxygen species; Vascular dysfunction