Peroxisome proliferator-activated receptor-α stimulation by clofibrate favors an antioxidant and vasodilator environment in a stressed left ventricle

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• 作者：Luz Ibarra-Lara^a ; Leonardo Del Valle-Mondragó ; n^a ; Elizabeth Soria-Castro^b ; Juan C. Torres-Narvá ; ez^a ; Francisca Pé ; rez-Severiano^c ; Marí ; a Sá ; nchez-Aguilar^a ; Margarita Ramí ; rez-Ortega^a ; Luz G. Cervantes-Pé ; rez^a ; Gustavo S. Pastelí ; n-Herná ; ndez^a ; Ví ; ctor H. Oidor-Chan^d ; Gabriela Zarco-Olvera^a ; Alicia Sá ; nchez-Mendoza^a ; ^{masanchez@gmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Target organ damage ; PPAR-α ; Stressed left ventricle
• 刊名：Pharmacological Reports
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：68
• 期：4
• 页码：692-702
• 全文大小：1766 K

文摘

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.

Methods

Male Wistar rats were assigned to Control (Sham)- or aortic coarctation-surgery and further divided to receive (1 or 21 days) vehicle, clofibrate (100 mg/kg), captopril (20 mg/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.

Results

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.

Conclusions

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.