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


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.
Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico.
Luz
L
Ibarra-Lara
Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico.
Leonardo
L
Del Valle-Mondragón
Department of Pathology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico.
Elizabeth
E
Soria-Castro
Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico.
Juan C
JC
Torres-Narváez
Department of Neurochemistry, National Institute of Neurology and Neurosurgery Manuel Velasco Suárez, Mexico City, Mexico.
Francisca
F
Pérez-Severiano
Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico.
María
M
Sánchez-Aguilar
Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico.
Margarita
M
Ramírez-Ortega
Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico.
Luz G
LG
Cervantes-Pérez
Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico.
Gustavo S
GS
Pastelín-Hernández
Department of Pharmacobiology, Research and Advanced Studies Center of National Polytechnic Institute, Mexico City, Mexico.
Víctor H
VH
Oidor-Chan
Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico.
Gabriela
G
Zarco-Olvera
Department of Pharmacology, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico. Electronic address: masanchez@gmail.com.
Alicia
A
Sánchez-Mendoza
D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001017:Aortic Coarctation / Q000150:complications / Q000503:physiopathology; D002216:Captopril / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D002994:Clofibrate / Q000494:pharmacology*; D004357:Drug Synergism; D006352:Heart Ventricles / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists*; D010446:Peptide Fragments / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D000975:Antioxidants; D047493:PPAR alpha; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D000803:Angiotensin I; D002216:Captopril; D002374:Catalase; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D002994:Clofibrate; C118790:angiotensin I (1-7)
PPAR-α; Stressed left ventricle; Target organ damage