Peroxisome proliferator-activated receptor β stimulation induces rapid cardiac growth and angiogenesis via direct activation of calcineurin

Wagner, Nicole; Jehl-Piétri, Chantal; Lopez, Pascal; Murdaca, Joseph; Giordano, Christian; Schwartz, Chantal; Gounon, Pierre; Hatem, Stéphane N.; Grimaldi, Paul A.; Wagner, Kay-Dietrich

doi:10.1093/cvr/cvp106

Cited by 61 publications

(69 citation statements)

References 37 publications

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“…17,18 Chronic treatment with GW0742 strongly reduced the vascular remodeling in mesenteric arteries, suggesting that this may contribute to reduce blood pressure. The lack of inhibitory effects of GW0742 in cardiac hypertrophy despite the reduction of blood pressure may be explained by insufficient time of low systolic blood pressure to induce morphological regression and induction of rapid cardiac growth, as described previously in mice with either GW0742 or another PPAR␤ agonist GW501516, 19 which counterbalances the effects of reduced blood pressure and Ang II pathway activity. However, in spite of the lack of macroscopic changes, GW0742 reduced both the increased cardiomyocyte diameter and collagen accumulation in SHRs, indicating that it prevents the histopathologic consequences of hypertension, which is in agreement with inhibition of Ang II-induced collagen synthesis in response to PPAR␤ activation.…”

Section: Discussionmentioning

confidence: 82%

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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Section: Discussionmentioning

confidence: 82%

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

Zarzuelo

Jiménez²,

Galindo³

et al. 2011

Hypertension

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“…However, a number of studies have consistently suggested that PPAR-␦ induces angiogenesis, possibly by activating VEGFA expression (7,12,55). Therefore, understanding the molecular details of PPAR-␦ transactivation of VEGFA could shed light on possible roles of PPAR-␦ in tumor formation.…”

Section: Discussionmentioning

confidence: 99%

β-Catenin and Peroxisome Proliferator-activated Receptor-δ Coordinate Dynamic Chromatin Loops for the Transcription of Vascular Endothelial Growth Factor A Gene in Colon Cancer Cells

Hwang

Kim

Jeong

2012

Journal of Biological Chemistry

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Background: Mechanism of VEGFA transcription by complex interplay of ␤-catenin and PPAR-␦ remains elusive. Results: The VEGFA promoter was dynamically occupied by ␤-catenin, TCF-4, and PPAR-␦. ␤-Catenin also bound downstream region of the VEGFA gene. Conclusion: ␤-Catenin is responsible for the formation of chromatin loops, which is relieved by PPAR-␦ activation. Significance: Proposed mechanism could provide clues for VEGFA-mediated colon cancer cell initiation.

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“…[73][74][75] Moreover, PPARβ promotes physiological cardiac remodeling. 76 Based on these findings, PPAR agonists were proposed to be beneficial for treatment of heart failure. However, the currently available PPAR agonists show significant side effects, thereby limiting a general use.…”

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confidence: 99%

The Ubiquitin-Like SUMO System and Heart Function

Mendler

Braun

Müller

2016

Circulation Research

101

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Peroxisome proliferator-activated receptor β stimulation induces rapid cardiac growth and angiogenesis via direct activation of calcineurin

Abstract: Our data suggest PPARbeta pharmacological activation as a novel approach to increase cardiac vascularization and cardiac muscle mass.

Cited by 61 publications

References 37 publications

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

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

β-Catenin and Peroxisome Proliferator-activated Receptor-δ Coordinate Dynamic Chromatin Loops for the Transcription of Vascular Endothelial Growth Factor A Gene in Colon Cancer Cells

The Ubiquitin-Like SUMO System and Heart Function

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