Khuman Maibam Wanta, Harikumar Sankaran Kutty, Sadam Abdul, Kesavan Manickam, Susanth Vattaparambil Sukumaran, Parida Subhashree, Singh Karam Pal, Sarkar Souvendra Nath
Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
Centre for Animal Disease Research and Diagnosis, ICAR-Indian Veterinary Research Institute, Izatnagar - 243122, Bareilly, Uttar Pradesh, India.
Toxicology. 2016 Dec 30;374:29-41. doi: 10.1016/j.tox.2016.11.015. Epub 2016 Nov 23.
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 AT receptor (ATR) 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 AT, AT 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 AT 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.
接触砷可导致多种心血管疾病，包括高血压、动脉粥样硬化和微血管疾病。此前，我们报道过砷介导的血管紧张素II（AngII）信号增强会损害血管生理功能。在此，我们研究了AT受体（ATR）阻滞剂坎地沙坦是否能改善砷诱导的大鼠高血压血管重塑，以及这种改善是否与血管AngII和转化生长因子-β（TGF-β）信号的减弱有关。大鼠通过饮用含50ppm亚砷酸钠的水连续暴露90天。在砷暴露的最后30天，每天口服一次坎地沙坦（1mg/kg体重）。每周记录清醒大鼠的无创血压，在第91天通过有创方法测量麻醉大鼠中AngII诱导的平均动脉压变化。在这一天，从其他动物采集血液以测量AngII水平。对胸主动脉进行AT、AT和TβRII受体的蛋白质印迹分析；PTK、RasGAP、ERK-1/2、TGF-β和结缔组织生长因子（CTGF）的酶联免疫吸附测定（ELISA）；磷酸化Smad3、Smad4和胶原蛋白III的免疫组织化学分析、羟脯氨酸/总胶原蛋白估计、通过Masson三色染色法进行胶原蛋白沉积分析以及组织形态计量学分析。砷使无创收缩压、舒张压和平均动脉压升高。此外，AngII使砷暴露大鼠的平均动脉压产生浓度依赖性的增量变化。砷上调了AT和TβRII受体蛋白；升高了PTK、ERK-1/2、TGF-β和CTGF的水平，降低了RasGAP水平，并增强了Smad3、Smad4和胶原蛋白III的免疫反应性。砷还增加了羟脯氨酸/总胶原蛋白水平、胶原纤维增殖以及主动脉壁和胶原外膜的厚度。坎地沙坦使血压正常化，使受体表达、丝裂原活化蛋白激酶（MAP）和TGF-β信号恢复正常，恢复胶原蛋白沉积并使主动脉厚度消退。我们的结果表明，坎地沙坦可通过调节AngII和TGF-β的信号通路来改善砷介导的大鼠全身性高血压和血管重塑。
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