Endothelium-Dependent Vasodilator Effects of Peroxisome Proliferator-Activated Receptor β Agonists via the Phosphatidyl-Inositol-3 Kinase-Akt Pathway

Jiménez, Rosario; Sánchez, Manuel; Zarzuelo, María José; Romero, Miguel; Quintela, Ana María; López-Sepúlveda, R; Galindo, Pilar; Gómez-Guzmán, Manuel; Haro, Juan; Zarzuelo, Antonio; Pérez‐Vizcaíno, Francisco; Duarte, Juan

doi:10.1124/jpet.109.159806

Cited by 52 publications

(42 citation statements)

References 41 publications

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“…22 Whereas, PPARδ agonists GW0742 and L-165041 at higher concentrations (>1 μmol/L) can directly induce vasodilatation, eNOS phosphorylation, and NO production. 23 In addition, our recent study demonstrated that another PPARδ agonist GW1516 protects endothelial function in diabetic db/db mice through an increase of eNOS activity and NO production. 7 The present data show that PPARδ mediates the effect of metformin in increasing eNOS phosphorylation in both mouse aortae and MAECs, as well as NO production, which are consistent with aforementioned observations that PPARδ improves NO bioavailability.…”

Section: Discussionmentioning

confidence: 99%

Metformin Protects Endothelial Function in Diet-Induced Obese Mice by Inhibition of Endoplasmic Reticulum Stress Through 5′ Adenosine Monophosphate–Activated Protein Kinase–Peroxisome Proliferator–Activated Receptor δ Pathway

Cheang

Tian

Wong

et al. 2014

ATVB

167

114

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Objective— 5′ Adenosine monophosphate–activated protein kinase (AMPK) interacts with peroxisome proliferator–activated receptor δ (PPARδ) to induce gene expression synergistically, whereas the activation of AMPK inhibits endoplasmic reticulum (ER) stress. Whether the vascular benefits of antidiabetic drug metformin (AMPK activator) in diabetes mellitus and obesity is mediated by PPARδ remains unknown. We aim to investigate whether PPARδ is crucial for metformin in ameliorating ER stress and endothelial dysfunction induced by high-fat diet. Approach and Results— Acetylcholine-induced endothelium-dependent relaxation in aortae was measured on wire myograph. ER stress markers were determined by Western blotting. Superoxide production in mouse aortae and NO generation in mouse aortic endothelial cells were assessed by fluorescence imaging. Endothelium-dependent relaxation was impaired and ER stress markers and superoxide level were elevated in aortae from high-fat diet–induced obese mice compared with lean mice. These effects of high-fat diet were reversed by oral treatment with metformin in diet-induced obese PPARδ wild-type mice but not in diet-induced obese PPARδ knockout littermates. Metformin and PPARδ agonist GW1516 reversed tunicamycin (ER stress inducer)-induced ER stress, oxidative stress, and impairment of endothelium-dependent relaxation in mouse aortae as well as NO production in mouse aortic endothelial cells. Effects of metformin were abolished by cotreatment of GSK0660 (PPARδ antagonist), whereas effects of GW1516 were unaffected by compound C (AMPK inhibitor). Conclusions— Metformin restores endothelial function through inhibiting ER stress and oxidative stress and increasing NO bioavailability on activation of AMPK/PPARδ pathway in obese diabetic mice.

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Section: Discussionmentioning

confidence: 99%

Metformin Protects Endothelial Function in Diet-Induced Obese Mice by Inhibition of Endoplasmic Reticulum Stress Through 5′ Adenosine Monophosphate–Activated Protein Kinase–Peroxisome Proliferator–Activated Receptor δ Pathway

Cheang

Tian

Wong

et al. 2014

ATVB

167

114

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“…It has been convincingly reported that PI3K and Akt are important upstream regulators of eNOS activation. 27,28,[39][40][41][42] eNOSderived NO has been known to have a pivotal role in the modulation of vascular tone and function. 6,7 Taken together, our results allow us to propose that, ROS/RNS excess in peripheral resistance vessels during I/R injury may blunt PI3K/Akt/eNOS pathway, thus triggering endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that eNOS is a novel substrate for Akt and Akt has a key role in promoting endothelial NO production and vasorelaxation. 27,28 Therefore, the phosphorylation of Akt was tested. The results of western blot analysis revealed that Akt phosphorylation was reduced after I/R, although total Akt showed equal protein levels in all samples (Po0.01 vs sham; Figure 7b).…”

Section: Effects Of I/r and Ipc Treatment On Pi3k And Akt Expression mentioning

confidence: 99%

Delayed preconditioning prevents ischemia/reperfusion-induced endothelial injury in rats: role of ROS and eNOS

Zhao

et al. 2013

Laboratory Investigation

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Ischemic preconditioning (IPC) strongly protects against ischemia/reperfusion (I/R) injury; however, the molecular mechanism involved in delayed preconditioning-induced endothelial protection in peripheral arteries is unknown. Therefore, we examined using functional, morphologic and molecular biologic studies whether delayed IPC decreases formation of reactive oxygen species and upregulates endothelial nitric oxide synthase (eNOS) that in turn contributes to vascular endothelial protection. Adult male Sprague-Dawley rats were subjected to 30-min ischemia induced by mesenteric artery occlusion followed by 60-min reperfusion 24 h after sham surgery or preconditioning (three cycles of 5-min ischemia/5-min reperfusion). Delayed preconditioning prevented the I/R-induced impairment of endothelium-dependent relaxations to acetylcholine (maximal relaxation: sham 91.4 ± 2.2%; I/R 54.0 ± 4.0%; IPC 80.2 ± 6.3%). This protective effect was abolished by NOS inhibitor N G -nitro-L-arginine methyl ester and not changed by ascorbic acid. Electron microscopy showed marked endothelial damage after I/R and the ultrastructural changes were prevented by delayed preconditioning. Following I/R, the impairment of eNOS phosphorylation and expression was observed in mesenteric vessels. Furthermore, phosphatidylinositol 3-kinase (PI3K) and Akt phosphorylation were reduced, although total PI3K and Akt remained unchanged. IPC restored I/R-induced impairment of eNOS expression and activity. This was possibly the result of the recovery of PI3K/Akt phosphorylation. Furthermore, I/R increased serum level of malondialdehyde, intravascular superoxide and nitrotyrosine generation, which were abrogated by IPC. These results suggest that delayed preconditioning prevented I/R-induced endothelial injury in peripheral resistance vasculature, both in terms of functional and structural changes. Endothelial protection afforded by delayed IPC is associated with inhibition of oxidative stress and upregulation of PI3K/Akt/eNOS pathway.

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“…9 PPAR␤ agonists also induce vasodilator effects in isolated aortas and mesenteric and pulmonary arteries. 10,11 Furthermore, a PPAR␤ agonist reduced the right heart hypertrophy and right ventricular systolic pressure in an experimental model of pulmonary arterial hypertension induced by chronic hypoxia. 11 We hypothesized that the PPAR␤ agonist GW0742 would reduce blood pressure, improving vascular inflammation and endothelial function in the spontaneously hypertensive rat (SHR).…”

mentioning

confidence: 99%

Antihypertensive Effects of Peroxisome Proliferator-Activated Receptor-β Activation in Spontaneously Hypertensive Rats

Zarzuelo

Jiménez²,

Galindo³

et al. 2011

Hypertension

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Abstract-Activation of nuclear hormone receptor peroxisome proliferator-activated receptor ␤/␦ (PPAR␤) has been shown to improve insulin resistance and plasma high-density lipoprotein levels, but nothing is known about its effects in genetic hypertension. We studied whether the PPAR␤ agonist GW0742 might exert antihypertensive effects in spontaneously hypertensive rats (SHRs). The rats were divided into 4 groups, Wistar Kyoto rat-control, Wistar Kyoto rat-treated (GW0742, 5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 by oral gavage), SHR-control, and SHR-treated, and followed for 5 weeks. GW0742 induced a progressive reduction in systolic arterial blood pressure and heart rate in SHRs and reduced the mesenteric arterial remodeling, the increased aortic vasoconstriction to angiotensin II, and the endothelial dysfunction characteristic of SHRs. These effects were accompanied by a significant increase in endothelial NO synthase activity attributed to upregulated endothelial NO synthase and downregulated caveolin 1 protein expression. Moreover, GW0742 inhibited vascular superoxide production, downregulated p22 phox and p47 phox proteins, decreased both basal and angiotensin II-stimulated NADPH oxidase activity, inhibited extracellular-regulated kinase 1/2 activation, and reduced the expression of the proinflammatory and proatherogenic genes, interleukin 1␤, interleukin 6, or intercellular adhesion molecule 1. None of these effects were observed in Wistar Kyoto rats. PPAR␤ activation, both in vitro and in vivo, increased the expression of the regulators of G protein-coupled signaling proteins RGS4 and RGS5, which negatively modulated the vascular actions of angiotensin II. PPAR␤ activation exerted antihypertensive effects, restored the vascular structure and function, and reduced the oxidative, proinflammatory, and proatherogenic status of SHRs. We propose PPAR␤ as a new therapeutic target in hypertension. T he peroxisome proliferator-activated receptors (PPARs) PPAR␣, PPAR␤/␦, and PPAR␥ are members of the nuclear hormone receptor superfamily. PPARs were initially believed to regulate genes involved only in lipid and glucose metabolism. 1 However, in recent years, evidence suggests that activation of PPAR␣ or PPAR␥ may exert cardiovascular protection beyond their metabolic effects. 2 In fact, PPAR␣ or PPAR␥ agonists exert antihypertensive effects in both human and animal models with or without metabolic disorders. [3][4][5][6] The mechanisms underlying the beneficial effects of PPARs beyond glucose and lipid metabolism may relate to their anti-inflammatory and antioxidant actions. 5 Thus, activation of both PPAR␣ or PPAR␥ antagonizes angiotensin II (Ang II) actions, including the activation of NADPH oxidase and the generation of reactive oxygen species, as well as the increase in proinflammatory mediators and adhesion molecules in blood vessels. 5,6 Activation of PPAR␤/␦ (PPAR␤) also exhibits antiinflammatory properties in the vessel wall by inhibiting the expression of vascular cell adhesion molecule 1 and monocyte chemoattractant prote...

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Endothelium-Dependent Vasodilator Effects of Peroxisome Proliferator-Activated Receptor β Agonists via the Phosphatidyl-Inositol-3 Kinase-Akt Pathway

Cited by 52 publications

References 41 publications

Metformin Protects Endothelial Function in Diet-Induced Obese Mice by Inhibition of Endoplasmic Reticulum Stress Through 5′ Adenosine Monophosphate–Activated Protein Kinase–Peroxisome Proliferator–Activated Receptor δ Pathway

Metformin Protects Endothelial Function in Diet-Induced Obese Mice by Inhibition of Endoplasmic Reticulum Stress Through 5′ Adenosine Monophosphate–Activated Protein Kinase–Peroxisome Proliferator–Activated Receptor δ Pathway

Delayed preconditioning prevents ischemia/reperfusion-induced endothelial injury in rats: role of ROS and eNOS

Antihypertensive Effects of Peroxisome Proliferator-Activated Receptor-β Activation in Spontaneously Hypertensive Rats

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