Deletion of peroxisome proliferator-activated receptor-alpha induces an alteration of cardiac functions.

The peroxisome proliferator-activated receptor-alpha (PPARalpha) plays a major role in the control of cardiac energy metabolism. The role of PPARalpha on cardiac functions was evaluated by using PPARalpha knockout (PPARalpha -/-) mice. Hemodynamic parameters by sphygmomanometric measurements show that deletion of PPARalpha did not affect systolic blood pressure and heart rate. Echocardiographic measurements demonstrated reduced systolic performance as shown by the decrease of left ventricular fractional shortening in PPARalpha -/- mice. Telemetric electrocardiography revealed neither atrio- nor intraventricular conduction defects in PPARalpha -/- mice. Also, heart rate, P-wave duration and amplitude, and QT interval were not affected. However, the amplitude of T wave from PPARalpha -/- mice was lower compared with wild-type (PPARalpha +/+) mice. When the myocardial function was measured by ex vivo Langendorff's heart preparation, basal and beta-adrenergic agonist-induced developed forces were significantly reduced in PPARalpha-null mice. In addition, Western blot analysis shows that the protein expression of beta1-adrenergic receptor is reduced in hearts from PPARalpha -/- mice. Histological analysis showed that hearts from PPARalpha -/- but not PPARalpha +/+ mice displayed myocardial fibrosis. These results suggest that PPARalpha-null mice have an alteration of cardiac contractile performance under basal and under stimulation of beta1-adrenergic receptors. These effects are associated with myocardial fibrosis. The data shed light on the role of PPARalpha in maintaining cardiac functions.

Cyclooxygenase-2 expression and role of vasoconstrictor prostanoids in small mesenteric arteries from patients with Crohn's disease.

BACKGROUND: The present study investigates the vascular reactivity and the involvement of nitric oxide and prostanoids in regulating vasoconstriction of small mesenteric arteries from patients with Crohn's disease (CD) to understand the vascular component of this pathology. METHODS AND RESULTS: An increased production of proinflammatory cytokines (tumor necrosis factor-alpha and interleukins 1beta, 6, and 8) has been observed in biopsy specimens of inflammatory intestinal mucosa. However, contractile responses of small mesenteric arteries from CD patients in response to norepinephrine were not changed ex vivo when compared with controls. Exposure to either the nitric oxide synthase inhibitor N(G)-nitro-L-arginine or the cyclooxygenase (COX) inhibitor indomethacin did not modify contractions induced by norepinephrine in either control or CD patients. However, in the latter, the specific COX-2 inhibitor N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide significantly attenuated norepinephrine-induced vasoconstriction. Furthermore, immunohistochemical analysis showed marked COX-2 expression in the whole arterial wall of vessels from CD patients. Vessels from control patients exhibited weak COX-2 staining in the adventitial and endothelial layers only. CONCLUSIONS: The above results provide direct evidence for COX-2 expression in small mesenteric arteries from CD patients. They also shed new light on the involvement of vasoconstrictor metabolites of COX in regulating contraction of these arteries. Of particular interest is the balance between vasoconstrictor products from COX-2 and unidentified vasodilatory products that maintained vascular reactivity in a physiological range despite an increase of circulatory cytokines in patients with CD.

Cyclooxygenase-2 and inducible nitric oxide synthase in omental arteries harvested from patients with severe liver diseases: immuno-localization and influence on vascular tone.

OBJECTIVE: To investigate the expression of inducible cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) and the role of vasodilatory prostanoids and endogenous nitric oxide (NO) in small omental arteries harvested from patients with severe liver diseases. DESIGN: Ex vivo study of resistance arteries. SETTING. Intensive care unit. PATIENTS: Twenty patients undergoing liver transplantation for fulminant hepatic failure (FHF, n=6), cirrhogenous viral hepatitis (CH, n=6) and limited hepatocarcinoma (controls, n=8). INTERVENTIONS: Western blot and immunohistochemical labeling for assessment of COX-2 and iNOS expression and localization and ex vivo vascular reactivity studies. MEASUREMENTS AND RESULTS: Significant upregulation of COX-2 and iNOS expressions were detected in arteries from FHF and CH patients with a greater increase in the former than in the latter. Ex vivo contractile responses to norepinephrine and the thromboxane A(2) analog, U46619, were not significantly different between patients with severe liver dysfunction and controls. Exposure to either the NO-synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), the cyclooxygenase inhibitor, indomethacin, or their combination did not significantly modify contractions of agonists in controls and CH patients. In FHF, the specific COX-2 inhibitor, N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (1 micro m/l), but not L-NAME, significantly enhanced the maximal effect ( p<0.01) and the sensitivity ( p<0.01) to norepinephrine. CONCLUSIONS: COX-2 and iNOS are upregulated in omental arteries from patients with cirrhogenous hepatitis and fulminant hepatic failure. Whereas neither NO nor vasodilatory prostaglandins seem to play a major role in counteracting arterial contractility of arteries from control patients, COX-2 derivatives are involved in lowering the arterial contractility of vessels harvested from FHF patients.

Activation of the peroxisome proliferator-activated receptor alpha protects against myocardial ischaemic injury and improves endothelial vasodilatation.

BACKGROUND: The peroxisome proliferator-activated receptor alpha (PPARalpha) plays an important role in the metabolism of lipoproteins and fatty acids, and seems to protect against the development of atherosclerosis. To evaluate the possible protective role of PPARalpha on cardiovascular function, the effect of the PPARalpha agonist, fenofibrate was assessed with respect to ischaemia/reperfusion injury and endothelial function in mice. RESULTS: Fenofibrate treatment reduces myocardial infarction size and improves post-ischaemic contractile dysfunction. Hearts from PPARalpha null mice exhibit increased susceptibility to ischaemic damages and were refractory to protection by fenofibrate treatment suggesting that the beneficial effects of fenofibrate were mediated via PPARalpha. Furthermore, fenofibrate improves endothelium- and nitric oxide-mediated vasodilatation in aorta and mesenteric vascular bed. A decreased inhibitory effect of reactive oxygen species in the vessel wall accounts for enhanced endothelial vasodilatation. However, the latter cannot be explained by an increase in nitric oxide synthase expression nor by an increase sensitivity of the arteries to nitric oxide. CONCLUSIONS: Altogether the present data suggest that fenofibrate exerts cardioprotective effect against ischaemia and improves nitric oxide-mediated response probably by enhancing antioxidant capacity of the vessel wall. These data underscore new therapeutic perspectives for PPARalpha agonists in ischaemic myocardial injury and in cardiovascular diseases associated with endothelial dysfunction.