Ibarra-Lara Luz, Del Valle-Mondragón Leonardo, Soria-Castro Elizabeth, Torres-Narváez Juan C, Pérez-Severiano Francisca, Sánchez-Aguilar María, Ramírez-Ortega Margarita, Cervantes-Pérez Luz G, Pastelín-Hernández Gustavo S, Oidor-Chan Víctor H, Zarco-Olvera Gabriela, Sánchez-Mendoza Alicia
Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico.
Department of Pathology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico.
Pharmacol Rep. 2016 Aug;68(4):692-702. doi: 10.1016/j.pharep.2016.03.002. Epub 2016 Mar 21.
Arterial high blood pressure is a risk factor for target organ damage; the most susceptible organs are the arteries, brain, kidneys, and heart. The damage mechanisms include oxidative stress and renin-angiotensin system (RAS) overactivity. Therefore, our aim was to study whether clofibrate-induced peroxisome proliferator-activated receptor-alpha (PPAR-α) stimulation is able to prevent alterations in cardiac functioning derived from RAS overstimulation in the left ventricle of rats with hypertension secondary to aortic coarctation and to improve antioxidant defenses.
Male Wistar rats were assigned to Control (Sham)- or aortic coarctation-surgery and further divided to receive (1 or 21 days) vehicle, clofibrate (100mg/kg), captopril (20mg/kg), or clofibrate+captopril. The left ventricle was obtained to measure: angiotensin II and -(1-7), AT1 and AT2 receptors, angiotensin converting enzyme (ACE)-1 and -2, and MAS receptor; the activity and expression of superoxide dismutase, catalase, endothelial nitric oxide synthase, the production of reactive oxygen species (ROS) and peroxidated lipids; as well as ex vivo cardiac functioning.
Clofibrate decreased angiotensin II, AT1 receptor and ACE expression, and raised angiotensin-(1-7), AT2 receptor, ACE-2 expression, superoxide dismutase and endothelial nitric oxide synthase participation. These effects promoted lower coronary vascular resistance and improved mechanical work compared to aortic coarctated vehicle-treated rats.
Clofibrate-induced PPAR-α stimulation changes the angiotensin II receptor profile, favors the ACE2/angiotensin-(1-7)/AT2 receptor axis decreasing the vasoconstrictor environment, activates the antioxidant defense, and facilitates endothelial nitric oxide synthase activity favoring vasodilation. This may represent a protection for the stressed heart.
动脉高血压是靶器官损伤的危险因素；最易受影响的器官是动脉、脑、肾和心脏。损伤机制包括氧化应激和肾素 - 血管紧张素系统（RAS）过度激活。因此，我们的目的是研究氯贝丁酯诱导的过氧化物酶体增殖物激活受体 -α（PPAR -α）刺激是否能够预防主动脉缩窄继发高血压大鼠左心室中RAS过度刺激引起的心脏功能改变，并改善抗氧化防御。
将雄性Wistar大鼠分为对照组（假手术组）或主动脉缩窄手术组，并进一步分为接受（1或21天）载体、氯贝丁酯（100mg/kg）、卡托普利（20mg/kg）或氯贝丁酯 + 卡托普利的组。获取左心室以测量：血管紧张素II和 -（1 - 7）、AT1和AT2受体、血管紧张素转换酶（ACE）-1和 -2以及MAS受体；超氧化物歧化酶、过氧化氢酶、内皮型一氧化氮合酶的活性和表达、活性氧（ROS）和过氧化脂质的产生；以及离体心脏功能。
氯贝丁酯降低了血管紧张素II、AT1受体和ACE的表达，并提高了血管紧张素 -（1 - 7）、AT2受体、ACE -2的表达、超氧化物歧化酶和内皮型一氧化氮合酶的参与度。与主动脉缩窄载体处理的大鼠相比，这些作用促进了更低的冠状动脉血管阻力并改善了机械功。
氯贝丁酯诱导的PPAR -α刺激改变了血管紧张素II受体谱，有利于ACE2/血管紧张素 -（1 - 7）/AT2受体轴，降低血管收缩环境，激活抗氧化防御，并促进内皮型一氧化氮合酶活性，有利于血管舒张。这可能代表了对压力心脏的一种保护。
