title: Candesartan ameliorates arsenic-induced hypertensive vascular remodeling by regularizing angiotensin II and TGF-beta signaling in rats.
abstract: Arsenic exposure can cause several cardiovascular diseases, including hypertension, atherosclerosis and microvascular disease. Earlier, we reported that arsenic-mediated enhancement of angiotensin II (AngII) signaling can impair vascular physiology. Here, we investigated whether the AT1receptor (AT1R) blocker candesartan can ameliorate the arsenic-induced hypertensive vascular remodeling in rats and whether the amelioration could relate to attenuation in vascular AngII and TGF-β signaling. Rats were exposed to sodium arsenite (50ppm) through drinking water for 90 consecutive days. Candesartan (1mg/kg bw, orally) was administered once daily during the last 30days of arsenic exposure. Non-invasive blood pressure was recorded weekly in conscious rats, while AngII-induced change in mean arterial pressure in anaesthetized rats was measured by invasive method on the 91st day. On this day, blood was collected from other animals for measuring AngII level. Western blot of AT1, AT2and TβRII receptors; ELISA of PTK, RasGAP, ERK-1/2, TGF-β and CTGF; immunohistochemistry of phosphorylated Smad3, Smad4 and collagen III, hydroxyproline/total collagen estimation, collagen deposition by Masson's trichrome staining and histomorphometry were carried out in thoracic aorta. Arsenic increased non-invasive systolic, diastolic and mean arterial pressure. Further, AngII caused concentration-dependent incremental change in mean arterial pressure in the arsenic-exposed rats. Arsenic upregulated AT1and TβRII receptor proteins; elevated the levels of PTK, ERK-1/2, TGF-β and CTGF, decreased RasGAP level and augmented the immunoreactivities of Smad3, Smad4 and collagen III. Arsenic also increased hydroxyproline/total collagen level, proliferation of collagen fibres and thickness of aortic wall and collagenous adventitia. Candesartan normalized blood pressure, regularized receptor expressions, MAP kinase and TGF-β signaling, restored collagen deposition and regressed aortic thickness. Our results demonstrate that candesartan can ameliorate the arsenic-mediated systemic hypertension and vascular remodeling in rats by regularizing the signaling pathways of AngII and TGF-β.
authors.affiliation: Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Maibam Wanta
authors.initials: MW
authors.lastname: Khuman
authors.affiliation: Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Sankaran Kutty
authors.initials: SK
authors.lastname: Harikumar
authors.affiliation: Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Abdul
authors.initials: A
authors.lastname: Sadam
authors.affiliation: Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Manickam
authors.initials: M
authors.lastname: Kesavan
authors.affiliation: Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Vattaparambil Sukumaran
authors.initials: VS
authors.lastname: Susanth
authors.affiliation: Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Subhashree
authors.initials: S
authors.lastname: Parida
authors.affiliation: Centre for Animal Disease Research and Diagnosis, ICAR-Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
authors.forename: Karam Pal
authors.initials: KP
authors.lastname: Singh
authors.affiliation: Division of Pharmacology and Toxicology, ICAR-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 / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D020261:Arsenic Poisoning / Q000188:drug therapy* / Q000473:pathology*; D018053:Arsenites / Q000037:antagonists & inhibitors / Q000633:toxicity; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D017670:Sodium Compounds / Q000037:antagonists & inhibitors / Q000633:toxicity; D013777:Tetrazoles / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D018053:Arsenites; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D051785:Smad Proteins; D017670:Sodium Compounds; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; C017947:sodium arsenite; D003094:Collagen; C081643:candesartan
keywords: Angiotensin II; Arsenic; Candesartan; Hypertension; Signaling; TGF-β; Vascular fibrosis