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.

PPARα Stimulation Modulates Myocardial Ischemia-induced Activation of Renin-Angiotensin System.

We have recently demonstrated that peroxisome proliferator-activated receptor alpha (PPARα) stimulation lowers the production of angiotensin II while increasing the production of Ang-(1-7), both in cardiac and plasmatic level. This stimulation improves nitric oxide bioavailability, preserving cardiac histologic features and functioning. Based on these results, we decided to study the effect of PPARα stimulation on renin-angiotensin system components of ischemic myocardium. Male Wistar rats (weighing 300-350 g) were assigned to the following groups: (1) sham, (2) myocardial ischemia vehicle-treated (MI-V), and (3) myocardial ischemia clofibrate-treated. Expression of the angiotensin-converting enzyme increased during ischemia, whereas clofibrate-treated group remained comparable to control. Activation of the PPARα receptor stimulated the expression of angiotensin-converting enzyme-2; while the activity of this enzyme was increased in MI-V, clofibrate inhibited any change. The concentration of bradykinin and phospho-Akt(SER473) in homogenate increased in the animals treated with the drug. Mas receptor expression increased in MI-V rats. In conclusion, stimulation of PPARα by clofibrate prevents an increase in the activity of renin-angiotensin system and promotes the production of vasodilator substances.

Clofibrate PPARα activation reduces oxidative stress and improves ultrastructure and ventricular hemodynamics in no-flow myocardial ischemia.

Peroxisome proliferator-activated receptors (PPAR) play a critical physiological role in energy homeostasis, in inflammation, and a protective role in cardiovascular function. We assessed the antioxidant effect of clofibrate-induced Peroxisome proliferator-activated receptor alpha (PPARα) stimulation on ischemic myocardium on myocardial morphology and hemodynamics. Male Wistar rats (300 g) were distributed into the following groups: (1) Sham, (2) myocardial ischemia vehicle treated (MI-V), and (3) myocardial ischemia clofibrate [100 mg/kg/ intraperitoneally) treated (MI-C). Reactive oxygen species (ROS) and lipid peroxidation increased in MI-V, whereas clofibrate prevented this effect. Superoxide dismutase (SOD)-1 and SOD-2 expression increased 4 times upon PPARα stimulation. SOD-1, SOD-2, and catalase activity also increased in response to clofibrate. eNOS mRNA and tetrahydrobiopterin increased in the MI-C group. Clofibrate was able to decrease Angiotensin II (AngII), AngII AT1-receptor, whereas Ang-(1-7) and AngII AT2-receptor expression increased. Assessment of myocardial morphology and cardiac function show that clofibrate improved histological features and hemodynamic parameters. Our results suggest that PPARα stimulation by clofibrate increases the antioxidant defense, leading to improved cardiac function.

PPARalpha stimulation exerts a blood pressure lowering effect through different mechanisms in a time-dependent manner.

Peroxisome proliferator activated receptors (PPARs) are a family of nuclear receptors that, upon activation with selective ligands, work as transcription factors. Recently, these have been related with the cardiovascular system. Our aim was to study PPARalpha-stimulation and its effects on blood pressure in rats with aortic coarctation, and to explore the role of the antioxidant system. Male Wistar rats (250-280 g) were distributed into the following groups: 1) sham; 2) aortic coarctated-vehicle-treated (AoCo-V), and 3) AoCo-clofibrate (100mg/kg) treated (AoCo-C). Rats were treated for 1 or 21 days. Clofibrate lowered blood pressure in both 1- and 21-day treatments. Renal reactive oxygen species increased after 1 day in AoCo-V, while clofibrate prevented this effect. Superoxide dismutase (SOD)-1 expression increased 3.6-fold upon PPARalpha stimulation (1 day) and returned to normal values by day 21. SOD-1 activity increased slightly in response to clofibrate. Renal activity of catalase increased in AoCo-C (1 day) and returned to normal (21 days). eNOS expression was not modified acutely (1 day) but increased at 21 days of treatment with clofibrate. Angiotensin II AT(1)-receptor expression as well as angiotensin II decreased in clofibrate-treated rats, while angiotensin II AT(2)-receptor expression increased, in both treatment periods. Angiotensin-(1-7) increased at 21 days. Our results suggest that in the early development of AoCo-induced hypertension, stimulation of PPARalpha increases the antioxidant defenses, leading to improvement in endothelial factors while in the sub-chronic phase (21 days), eNOS and angiotensin II receptors appear to play major roles in controlling blood pressure.