Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
Life Sci. 2019 Dec 15;239:117047. doi: 10.1016/j.lfs.2019.117047. Epub 2019 Nov 12.
Peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, pioglitazone, is used clinically to improve the glycemic state in patients with type-2 diabetes mellitus. Independent of its blood glucose-lowering properties, pioglitazone ameliorates different cardiovascular disorders. The aim of the present study was to investigate the effect of pioglitazone on cardiovascular complications of N-nitro-L-arginine methyl ester (L-NAME)-induced hypertension and to determine the role of oxidative and endoplasmic reticulum (ER) stress in its activity. Nitric oxide (NO) deficiency induced by chronic L-NAME administration was associated with high blood pressure (BP) and cardiac hypertrophy. L-NAME induced oxidative stress as indicated by reduced glutathione (GSH) levels, superoxide dismutase (SOD) and catalase activities as well as increased malondialdehyde (MDA) levels. Furthermore, L-NAME increased the expression of ER stress markers, activating transcription factor-4 (ATF-4) and C/EPBα-homologous protein-10 (CHOP-10) in both heart and aorta of hypertensive rats. Activation of PPAR-γ by pioglitazone reduced BP, restored the blunted NO levels, increased endothelial NO synthase (eNOS) expression, and restored the antioxidant status of L-NAME-induced hypertensive rats. Moreover, the antihypertensive activity of pioglitazone was associated with a reduction in ER stress and this effect was PPAR-γ dependent. Interestingly, the effect of ER stress inhibitor, 4-phenylbutyric acid (4-PBA) and antioxidant, N-acetylcysteine (NAC), on BP, NO availability, oxidative stress and ER stress mimics the activity of pioglitazone. Taken together, our data suggests that PPAR-γ is a potential target to inhibit vascular complications and cardiac damage associated with NO-deficient HTN and puts more emphasis on the importance of ER stress in regulating PPAR-γ activity.
过氧化物酶体增殖物激活受体 γ（PPAR-γ）激动剂吡格列酮临床上用于改善 2 型糖尿病患者的血糖状态。吡格列酮除了降低血糖作用外，还能改善多种心血管疾病。本研究旨在探讨吡格列酮对 N-硝基-L-精氨酸甲酯（L-NAME）诱导的高血压心血管并发症的影响，并确定氧化应激和内质网（ER）应激在其活性中的作用。慢性 L-NAME 给药诱导的一氧化氮（NO）缺乏与高血压和心肌肥厚有关。L-NAME 诱导的氧化应激表现为还原型谷胱甘肽（GSH）水平降低、超氧化物歧化酶（SOD）和过氧化氢酶活性降低以及丙二醛（MDA）水平升高。此外，L-NAME 增加了高血压大鼠心脏和主动脉中 ER 应激标志物激活转录因子-4（ATF-4）和 C/EPBα 同源蛋白-10（CHOP-10）的表达。PPAR-γ 的激活通过吡格列酮降低血压，恢复减弱的 NO 水平，增加内皮型一氧化氮合酶（eNOS）的表达，并恢复 L-NAME 诱导的高血压大鼠的抗氧化状态。此外，吡格列酮的降压作用与 ER 应激的减少有关，这种作用依赖于 PPAR-γ。有趣的是，ER 应激抑制剂 4-苯丁酸（4-PBA）和抗氧化剂 N-乙酰半胱氨酸（NAC）对血压、NO 可用性、氧化应激和 ER 应激的作用类似于吡格列酮的作用。总之，我们的数据表明，PPAR-γ 是抑制与 NO 缺乏性 HTN 相关的血管并发症和心脏损伤的潜在靶点，并更加重视 ER 应激在调节 PPAR-γ 活性中的重要性。
