Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC

Murakami, Hisashi; Murakami, Ryuichiro; Kambe, Fukushi; Cao, Xia; Takahashi, Ryōsuke; Asai, Tomohiro; Hirai, Tatsuya; Numaguchi, Yasushi; Okumura, Kenji; Seo, Hisao; Murohara, Toyoaki

doi:10.1016/j.bbrc.2006.01.052

Cited by 77 publications

(72 citation statements)

References 23 publications

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“…However, phosphorylation of eNOS at Ser-1177, a valuable marker for active eNOS enzyme, was transiently increased by the compound. Similar observations have been described with fenofibrate [44] . We could not confirm the fenofibrate results with our cellular setup.…”

Section: Comparison Of Ave8134 To Other Pparα Agonistssupporting

confidence: 89%

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats

Linz

Wohlfart

Baader³

et al. 2009

Acta Pharmacol Sin

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Aim: To investigate the efficacy of the peroxisome proliferator-activated receptor-α (PPARα) agonist, AVE8134, in cellular and experimental models of cardiac dysfunction and heart failure. Methods: In Sprague Dawley rats with permanent ligation of the left coronary artery (post-MI), AVE8134 was compared to the PPARγ agonist rosiglitazone and in a second study to the ACE inhibitor ramipril. In DOCA-salt sensitive rats, efficacy of AVE8134 on cardiac hypertrophy and fibrosis was investigated. Finally, AVE8134 was administered to old spontaneously hypertensive rats (SHR) at a nonblood pressure lowering dose with survival as endpoint. In cellular models, we studied AVE8134 on hypertrophy in rat cardiomyocytes, nitric oxide signaling in human endothelial cells (HUVEC) and LDL-uptake in human MonoMac-6 cells. Results: In post-MI rats, AVE8134 dose-dependently improved cardiac output, myocardial contractility and relaxation and reduced lung and left ventricular weight and fibrosis. In contrast, rosiglitazone exacerbated cardiac dysfunction. Treatment at AVE8134 decreased plasma proBNP and arginine and increased plasma citrulline and urinary NOx/creatinine ratio. In DOCA rats, AVE8134 prevented development of high blood pressure, myocardial hypertrophy and cardiac fibrosis, and ameliorated endothelial dysfunction. Compound treatment increased cardiac protein expression and phosphorylation of eNOS. In old SHR, treatment with a low dose of AVE8134 improved cardiac and vascular function and increased life expectancy without lowering blood pressure. AVE8134 reduced phenylephrine-induced hypertrophy in adult rat cardiomyocytes. In HUVEC, Ser-1177-eNOS phosphorylation but not eNOS expression was increased. In monocytes, AVE8134 increased the expression of CD36 and the macrophage scavenger receptor 1, resulting in enhanced uptake of oxidized LDL. Conclusion: The PPARα agonist AVE8134 prevents post-MI myocardial hypertrophy, fibrosis and cardiac dysfunction. AVE8134 has beneficial effects against hypertension-induced organ damages, resulting in decreased mortality. The compound exerts its protective properties by a direct effect on cardiomyocyte hypertrophy, but also indirectly via monocyte signaling and increased endothelial NO production.

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Section: Comparison Of Ave8134 To Other Pparα Agonistssupporting

confidence: 89%

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats

Linz

Wohlfart

Baader³

et al. 2009

Acta Pharmacol Sin

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“…The ability of fenofibrate to increase NO production in endothelial cells has previously been demonstrated. For example, in cultured human umbilical vein endothelial cells (HUVECs), fenofibrate (30μM; 10 minutes) treatment resulted in a ~2-fold increase in NO production, (37) in line with the increases observed in our study. Similarly, a 2-fold increase in NO production was observed in human glomerular microvascular endothelial cells treated with fenofibrate (100μM) for 1 hour.…”

Section: Discussionsupporting

confidence: 90%

“…Tomizawa, et al (2011) showed that 100μM fenofibrate activates AMPK and Akt in human glomerular microvascular endothelial cells with resultant activation of eNOS (Ser 1177) within 1 hour of treatment. Similarly, Murakami, et al (2006) demonstrated that fenofibrate activates AMPK and eNOS (Ser 1177) in HUVECs. These findings were observed at a concentration of 30μM at 10 minutes.…”

Section: Discussionmentioning

confidence: 90%

“…The up-regulation of eNOS activation was associated with a ~40% increase in NO generation compared to TNF-alpha only. Indeed, many of the pleiotropic effects of fenofibrate on vascular endothelium have been attributed to eNOS phosphorylation and activation; (9,37,38) however, most studies have not investigated fenofibrateinduced effects on the eNOS-NO biosynthesis pathway in the context of injured or dysfunctional endothelial cells. AMPK and Akt are regarded as two of the most important upstream regulators of eNOS activation via Ser 1177 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…(48) In the present study, fenofibrate pretreatment increased activated AMPK (phospho AMPK Thr 172) levels compared to TNF-alpha only treatment, which corresponds with the increased activation of eNOS. In this regard, fenofibrate has previously been associated with increased phosphorylation of AMPK (Thr 172) in a variety of endothelial cell types; (9,37,49,50) however, none of these studies were conducted in the context of TNF-alpha induced injury. Tomizawa, et al (2011) showed that 100μM fenofibrate activates AMPK and Akt in human glomerular microvascular endothelial cells with resultant activation of eNOS (Ser 1177) within 1 hour of treatment.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Fenofibrate protects endothelial cells against the harmful effects of TNF-alpha

Westcott

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Mthethwa

et al. 2017

SAHJ

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Comparisons of pharmacokinetics and NO‐releasing of nitrofibriate and fenofibrate after oral administration in rats

Yang

Cheng²,

Liu

et al. 2016

Biomedical Chromatography

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Nitrofibriate, a new compound of hypolipidemic, is modified based on fenofibrate. Both of them are used for prevention and treatment of cardiovascular diseases. In this study, an accurate and sensitive analytical method of reversed-phase high-performance liquid chromatography was developed to determine fenofibric acid, which is an active metabolite of both nitrofibriate and fenofibrate in rat plasma. This method was validated and successfully applied to pharmacokinetic study of nitrofibriate and fenofibrate after oral administration. The results suggested that the pharmacokinetic behavior of nitrofibriate followed a nonlinear process, while fenofibrate was linear, demonstrating that the two drugs were different in pharmacokinetic behaviors. Moreover, the effect of fenofibrate and nitrofibriate on releasing NO in rat serum was explored. This study showed that nitrofibriate, as a nitric oxide donor, could slowly release nitric oxide in vivo. This study provided a biopharmaceutical basis for further study of nitrofibriate.

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Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC

Cited by 77 publications

References 23 publications

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats

Fenofibrate protects endothelial cells against the harmful effects of TNF-alpha

Comparisons of pharmacokinetics and NO‐releasing of nitrofibriate and fenofibrate after oral administration in rats

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