PPARα-Independent Arterial Smooth Muscle Relaxant Effects of PPARαAgonists

Abstract

We sought to determine direct vascular effects of peroxisome proliferator-activated receptor alpha (PPARα) agonists using isolated mouse aortas and middle cerebral arteries (MCAs). The PPARα agonists GW7647, WY14643, and gemfibrozil acutely relaxed aortas held under isometric tension and dilated pressurized MCAs with the following order of potency: GW7647≫WY14643>gemfibrozil. Responses were endothelium-independent, and the use of PPARα deficient mice demonstrated that responses were also PPARα-independent. Pretreating arteries with high extracellular K+ attenuated PPARα agonist-mediated relaxations in the aorta, but not in the MCA. In the aorta, the ATP sensitive potassium (KATP) channel blocker glibenclamide also impaired relaxations whereas the other K+ channel inhibitors, 4-aminopyridine and Iberiotoxin, had no effect. In aortas, GW7647 and WY14643 elevated cGMP levels by stimulating soluble guanylyl cyclase (sGC), and inhibition of sGC with ODQ blunted relaxations to PPARα agonists. In the MCA, dilations were inhibited by the protein kinase C (PKC) activator, phorbol 12,13-dibutyrate, and also by ODQ. Our results demonstrated acute, nonreceptor-mediated relaxant effects of PPARα agonists on smooth muscle of mouse arteries. Responses to PPARα agonists in the aorta involved KATP channels and sGC, whereas in the MCA the PKC and sGC pathways also appeared to contribute to the response.

Peroxisome Proliferator-Activated Receptors Features, Functions, and Future

“…In support of a nongenomic effects, a study has shown that PPAR agonists of various chemical structures rapidly diminished ERK phosphorylation in human microvascular endothelial cells in parallel to their known receptor binding affinity [178]. Similarly, our recent findings showing a fast, PPAR -mediated, enhanced cardiac muscle contractility and blood vessel relaxation is in support of the existence of such nongenomic receptor pathways [179]. Furthermore, a most recent study has demonstrated that pioglitazone, a PPAR agonist, rapidly reduced neuropathic pain through non-genomic PPAR mechanisms [180].…”

FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability

“…Segments 3-4 mm in length were mounted on pins in chambers of a DMT 610M wire myograph system (Danish Myo Technology, Aarhus N, Denmark) containing Krebs buffer (in mM: 119 NaCl, 4.7 KCl, 0.24 NaHCO 3, 1.18 KH 2PO4, 1.19 MgSO4, 5.5 glucose, and 1.6 CaCl2) saturated at 37°C with a gas mixture containing 20% O 2-5% CO2-75% N2 (Airgas Mid-South, Tulsa, OK) at 37°C. Arterial rings were progressively stretched to 0.75 g equivalent force passive tension in 0.1 g steps and allowed to equilibrate for 45 min as described previously (58,59). Force changes were recorded using an ADinstruments (Colorado Springs, CO) PowerLab 4/30 and associated LabChart Pro software (v. 6.1) running on a standard Windows XP computer platform.…”

PPARα-independent action against metabolic syndrome development by fibrates is mediated by inhibition of STAT3 signalling

“…In isolated mouse aortas and middle cerebral arteries, the tension of middle cerebral arteries was inhibited by GW7647, WY14643 and gemfibrozil. But it was negative in PPARα‐deficient mice, demonstrating that actions were PPARα‐independent . In mice treated with a PPARα activator, the smooth muscle cell proliferation, tissue factor expression and neointimal formation were observed only in Ppara‐ null mice .…”

“…But it was negative in PPARadeficient mice, demonstrating that actions were PPARaindependent. [46] In mice treated with a PPARa activator, the smooth muscle cell proliferation, tissue factor expression and neointimal formation were observed only in Ppara-null mice. [47] In this study, MS symptoms developed in Pparanull mice and they were inhibited by low dose of gemfibrozil and fenofibrate, respectively.…”