Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Department of Pharmacology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.
Cardiovascular Disease Program, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia; Department of Pharmacology, Monash Biomedicine Discovery Institute (BDI), Monash University, Clayton, VIC, Australia.
Biomed Pharmacother. 2023 Sep;165:115238. doi: 10.1016/j.biopha.2023.115238. Epub 2023 Aug 1.
Stimulation of the angiotensin II type 2 receptor (ATR) evokes protective effects in various cardiovascular diseases. Thus, this study aimed to investigate the effects of ATR stimulation, with or without ATR blockade, in a model of hypertension with concomitant type 1 diabetes mellitus (T1DM). Spontaneously hypertensive rats (SHRs) were given either citrate or a single dose of streptozotocin (STZ; 55 mg/kg, i.p.) to induce diabetes. After 4 weeks of diabetes, animals were administered either a vehicle (saline), ATR agonist, β-ProAng III (0.1 mg/kg/day via osmotic mini-pump), ATR blocker, candesartan (2 mg/kg/day via drinking water), or a combination of both for a further 8 weeks. β-ProAng III treatment had no effect on blood pressure, but attenuated the significant increase in cardiac interstitial collagen and protein expression of fibrotic and inflammatory markers, and superoxide levels that was evident in diabetic SHRs. These effects were not observed with candesartan, despite its blood pressure lowering effects. Although β-ProAng III had no effect on aortic fibrosis, it significantly attenuated MCP-1 protein expression and superoxide levels when compared to both the non-diabetic and diabetic SHRs, to a similar extent as candesartan. In both the heart and vasculature, the effects of β-ProAng III in combination with candesartan were similar to those of β-ProAng III alone, and superior to candesartan alone. It was concluded that in hypertension with concomitant diabetes, ATR stimulation with a novel ligand alone, or in combination with ATR blockade, improved the cardiac and vascular structural changes that were strongly associated with inflammation and oxidative stress, independent of blood pressure regulation.
血管紧张素 II 型受体（ATR）的刺激在各种心血管疾病中产生保护作用。因此，本研究旨在研究ATR 刺激（伴有或不伴有 ATR 阻断）在伴有 1 型糖尿病（T1DM）的高血压模型中的作用。自发性高血压大鼠（SHR）给予柠檬酸盐或单次链脲佐菌素（STZ；55mg/kg，腹腔注射）诱导糖尿病。糖尿病 4 周后，动物给予载体（生理盐水）、ATR 激动剂β-ProAng III（0.1mg/kg/天通过渗透微型泵）、ATR 阻滞剂坎地沙坦（2mg/kg/天通过饮用水）或两者的组合，进一步治疗 8 周。β-ProAng III 治疗对血压没有影响，但减轻了糖尿病 SHR 中明显增加的心肌间质胶原和纤维化及炎症标志物的蛋白表达以及超氧化物水平。坎地沙坦虽有降压作用，但未观察到这些作用。尽管β-ProAng III 对主动脉纤维化没有影响，但与非糖尿病和糖尿病 SHR 相比，其显著降低了 MCP-1 蛋白表达和超氧化物水平，与坎地沙坦的作用相似。在心脏和血管中，β-ProAng III 与坎地沙坦联合使用的效果与β-ProAng III 单独使用的效果相似，且优于坎地沙坦单独使用的效果。结论是，在伴有糖尿病的高血压中，新型配体单独或与 ATR 阻断联合刺激 ATR，可改善与炎症和氧化应激密切相关的心脏和血管结构变化，独立于血压调节。
