Effects of bezafibrate on the expression of endothelial nitric oxide synthase gene and its mechanisms in cultured bovine endothelial cells

Wang, Yan; Yang, Qi; Yan, Jun; Zhao, Chunxia; Cianflone, Katherine; Wang, Dao Wen

doi:10.1016/j.atherosclerosis.2005.09.008

Cited by 39 publications

(34 citation statements)

References 49 publications

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“…Thus the mechanism of the WY effect on the PI3K/Akt pathway involves its transcriptional upregulation via the activation of PPAR-␣. In accordance with our findings, the PPAR-␣ ligand bezafibrate was shown to increase eNOS expression at the transcriptional, posttranscriptional, and translational level in endothelial cells that involves the PPAR-␣-mediated activation of PI3K and the MAPK signaling pathways (39), suggesting that the effects of bezafibrate on eNOS in the endothelium are mediated by both genomic action through PPAR-␣ and a nongenomic manner through PI3K signaling pathways. iNOS expression was undetectable in the present study, suggesting that iNOS is not significantly upregulated during this brief ischemia-reper- fusion protocol in line with a previous observation (5).…”

Section: Discussionsupporting

confidence: 91%

“…We recently demonstrated that WY-14643 (WY), a selective agonist of PPAR-␣, exerts cardioprotection in a rat model of ischemia-reperfusion injury via mechanisms related to the production of nitric oxide (NO) and endothelin-1 (5). Moreover, PPAR-␣ ligands were reported to increase NO production via a mechanism involving the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in endothelial cells (29,39).…”

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confidence: 99%

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PPAR-α activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway

Bulhak

Jung²,

Östenson³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

109

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Bulhak AA, Jung C, Ö stenson C, Lundberg JO, Sjö quist P, Pernow J. PPAR-␣ activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-kinase/Akt and NO pathway. Am J Physiol Heart Circ Physiol 296: H719 -H727, 2009. First published January 16, 2009 doi:10.1152/ajpheart.00394.2008.-Several clinical studies have shown the beneficial cardiovascular effects of fibrates in patients with diabetes and insulin resistance. The ligands of peroxisome proliferatoractivated receptor-␣ (PPAR-␣) reduce ischemia-reperfusion injury in nondiabetic animals. We hypothesized that the activation of PPAR-␣ would exert cardioprotection in type 2 diabetic Goto-Kakizaki (GK) rats, involving mechanisms related to nitric oxide (NO) production via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. GK rats and agematched Wistar rats (n Ն 7) were given either 1) the PPAR-␣ agonist WY-14643 (WY), 2) dimethyl sulfoxide (DMSO), 3) WY and the NO synthase inhibitor N G -nitro-L-arginine (L-NNA), 4) L-NNA, 5) WY and the PI3K inhibitor wortmannin, or 6) wortmannin alone intravenously before a 35-min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), expression of endothelial NO synthase (eNOS), inducible NO synthase, and Akt as well as nitrite/ nitrate were determined. The IS was 75 Ϯ 3% and 72 Ϯ 4% of the area at risk in the Wistar and GK DMSO groups, respectively. WY reduced IS to 56 Ϯ 3% in Wistar (P Ͻ 0.05) and to 46 Ϯ 5% in GK rats (P Ͻ 0.001). The addition of either L-NNA or wortmannin reversed the cardioprotective effect of WY in both Wistar (IS, 70 Ϯ 5% and 65 Ϯ 5%, respectively) and GK (IS, 66 Ϯ 4% and 64 Ϯ 4%, P Ͻ 0.05, respectively) rats. The expression of eNOS and eNOS Ser1177 in the ischemic myocardium from both strains was increased after WY. The expression of Akt, Akt Ser473, and Akt Thr308 was also increased in the ischemic myocardium from GK rats following WY. Myocardial nitrite/nitrate levels were reduced in GK rats (P Ͻ 0.05). The results suggest that PPAR-␣ activation protects the type 2 diabetic rat myocardium against ischemia-reperfusion injury via the activation of the PI3K/Akt and NO pathway.peroxisome proliferator-activated receptor-␣ ligand; endothelial function; phosphatidylinositol 3-kinase

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

PPAR-α activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway

Bulhak

Jung²,

Östenson³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

109

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“…This suggests that AA is a key factor to produce NO in antral mucous cells, although an increase in [Ca 2+ ] i appears to be essential to stimulate AA accumulation via PLA 2 . NO synthesis stimulated by PPARα has already been shown in myocardium (5) and endothelial cells (16,30). Activation of PPARγ has also been reported to involve NO synthesis in endothelial cells (18).…”

Section: Discussionmentioning

confidence: 87%

“…Immunofluorescence examinations demonstrated that PPARα co-localizes with PI3K and Akt in the cytoplasm of antral mucous cells, and PPARα and NOS1 also co-localize in the cytoplasm of antral mucous cells (28). The PPARα ligands have been shown to phosphorylate PI3K/Akt in the endothelial cells (16,30). Thus, the activation of PPARα induces NOS1 phosphorylation mediated via the PI3K/Akt signal to produce NO in antral mucous cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, it remained uncertain how PPARα activates NOS1 in antral mucous cells. PPARα agonists have been shown to stimulate the NOS3 phosphorylation mediated via the phosphatidylinositol 3-kinase (PI3K)/ serine-threonine kinase (Akt) signal in endothelial cells (5,16,30). In myocardium and endothelial cells, there are reports showing that PPARγ stimulates NO synthesis via the PI3K/Akt signal (18).…”

mentioning

confidence: 99%

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PPARα induced NOS1 phosphorylation via PI3K/Akt in guinea pig antral mucous cells: NO-enhancement in Ca2+-regulated exocytosis

et al. 2016

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A PPARα (peroxisome proliferation activation receptor α) agonist (GW7647) activates nitric oxide synthase 1 (NOS1) to produce NO leading to cGMP accumulation in antral mucous cells. In this study, we examined how PPARα activates NOS1. The NO production stimulated by GW7647 was suppressed by inhibitors of PI3K (wortmannin) and Akt (AKT 1/2 Kinase Inhibitor, AKT-inh), although it was also suppressed by the inhibitors of PPARα (GW6471) and NOS1 (N-PLA). GW7647 enhanced the ACh (acetylcholine)-stimulated exocytosis (Ca 2+

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Enhancing the metabolic substrate: PPAR-alpha agonists in heart failure

2010

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The prognosis for patients diagnosed with heart failure has significantly improved over the past three decades; however, the disease still confers a high degree of morbidity and mortality. Current treatments for chronic heart failure have focused primarily on blocking neurohormonal signaling and optimizing hemodynamic parameters. Although significant resources have been devoted toward the development of new pharmaceutical therapies for heart failure, few new drugs have been designed to target myocardial metabolic pathways despite growing evidence that on a fundamental level chronic heart failure can be characterized as an imbalance between myocardial energy demand and supply. Disruptions in myocardial energy pathways are evident as the myocardium is unable to generate sufficient amounts of ATP with advancing stages of heart failure. Down-regulation of fatty acid oxidation likely contributes to the phenotype of the "energy starved" heart. Fibrates are small molecule agonists of PPARα pathways that have been used to treat dyslipidemia. Although never used therapeutically in clinical heart failure, PPARα agonists have been shown to enhance fatty acid oxidation, improve endothelial cell function, and decrease myocardial fibrosis and hypertrophy in animal models of heart failure. In light of their excellent clinical safety profile, PPARα agonists may improve outcomes in patients suffering from systolic heart failure by augmenting myocardial ATP production in addition to targeting maladaptive hypertrophic pathways.

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Effects of bezafibrate on the expression of endothelial nitric oxide synthase gene and its mechanisms in cultured bovine endothelial cells

Cited by 39 publications

References 49 publications

PPAR-α activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway

PPAR-α activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway

<b>PPARα induced NOS1 phosphorylation via PI3K/Akt in guinea pig antral mucous cells: NO-enhancement in Ca</b><sup><b>2+</b></sup><b>-regulated </b><b>exocytosis </b>

Enhancing the metabolic substrate: PPAR-alpha agonists in heart failure

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