Candesartan ameliorates arsenic-induced hypertensive vascular remodeling by regularizing angiotensin II and TGF-beta signaling in rats. (30th December 2016)

• Record Type: Journal Article
• Authors: Khuman, Maibam Wanta; Harikumar, Sankaran Kutty; Sadam, Abdul; Kesavan, Manickam; Susanth, Vattaparambil Sukumaran; Parida, Subhashree; Singh, Karam Pal; Sarkar, Souvendra Nath
• Is Part Of: Toxicology. Volume 374(2016)
• Page Start: 29
• Page End: 41
• Publication Date: 2016-12-30
• Subjects: AngII angiotensin II -- ARB angiotensin receptor blocker -- AT1R AT1 receptor -- AT2R AT2 receptor -- CVD cardiovascular disease -- DBP diastolic blood pressure -- CMC carboxymethyl cellulose -- CTGF connective tissue growth factor -- ECM extracellular matrix -- eNOS endothelial nitric oxide synthase -- ERK extracellular signal-regulated kinase -- FGF fibroblast growth factor -- IHC immunohistochemistry -- MAP mean arterial pressure -- MAPK mitogen-activated protein kinase -- PBS phosphate-buffered saline -- PDGF platelet-derived growth factor -- PKC protein kinase C -- pSmad3 phosphorylated Smad3 -- PTK protein tyrosine kinase -- SBP systolic blood pressure -- TBST tris-buffered saline-Tween-20 -- TGF-β transforming growth factor-beta -- TβRII TGF-β type II receptor -- VSMC vascular smooth muscle cell; Arsenic -- Hypertension -- Vascular fibrosis -- Angiotensin II -- TGF-β -- Signaling -- Candesartan; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2016.11.015
• Languages: English
• ISSNs: 0300-483X

Abstract

Highlights: Examined whether candesartan can ameliorate arsenic-induced vascular disorders. Arsenic caused systemic hypertension & also enhanced AngII-induced blood pressure. Arsenic elevated AngII & TGF-β levels; up-regulated aortic AT1 & TβRII receptors. Also increased transducers of MAPK & TGF-β pathways, aortic collagen & thickness. Candesartan reduced arsenic-induced functional, biochemical & structural changes. 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 AT1 receptor (AT1 R) 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 (50 ppm) through drinking water for 90 consecutive days. Candesartan (1 mg/kg bw, orally) was administered once daily during the last 30 days 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, AT2 and 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 AT1 and 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.