Recent advances in the understanding of the role of nitric oxide in cardiovascular homeostasis

Schulz, Rainer; Rassaf, Tienush; Massion, Paul; Kelm, Malte; Balligand, Jean‐Luc

doi:10.1016/j.pharmthera.2005.04.005

Cited by 131 publications

(99 citation statements)

References 411 publications

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“…This enzyme is activated by exendin-4 through phosphorylation, leading to enhanced NO production and this effect is dependent on the activation of the PI3K/Akt pathway (Erdogdu et al 2010). In addition, eNOS can also be activated by PKA or Akt, resulting in increased NO production (Schulz et al 2005). Previous work has indicated that the activity of eNOS is diminished in endothelial apoptosis induced by multiple proapoptotic factors (Dimmeler & Zeiher 1999).…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Erdogdu

Eriksson

et al. 2013

Journal of Molecular Endocrinology

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Experimental studies have indicated that endothelial cells play an important role in maintaining vascular homeostasis. We previously reported that human coronary artery endothelial cells (HCAECs) express the glucagon-like peptide 1 (GLP1) receptor and that the stable GLP1 mimetic exendin-4 is able to activate the receptor, leading to increased cell proliferation. Here, we have studied the effect of exendin-4 and native GLP1 (7-36) on lipoapoptosis and its underlying mechanisms in HCAECs. Apoptosis was assessed by DNA fragmentation and caspase-3 activation, after incubating cells with palmitate. Nitric oxide (NO) and reactive oxidative species (ROS) were analyzed. GLP1 receptor activation, PKA-, PI3K/Akt-, eNOS-, p38 MAPK-, and JNK-dependent pathways, and genetic silencing of transfection of eNOS were also studied. Palmitate-induced apoptosis stimulated cells to release NO and ROS, concomitant with upregulation of eNOS, which required activation of p38 MAPK and JNK. Exendin-4 restored the imbalance between NO and ROS production in which ROS production decreased and NO production was further augmented. Incubation with exendin-4 and GLP1 (7-36) protected HCAECs against lipoapoptosis, an effect that was blocked by PKA, PI3K/Akt, eNOS, p38 MAPK, and JNK inhibitors. Genetic silencing of eNOS also abolished the anti-apoptotic effect afforded by exendin-4. Our results support the notion that GLP1 receptor agonists restore eNOS-induced ROS production due to lipotoxicity and that such agonists protect against lipoapoptosis through PKA-PI3K/Akt-eNOS-p38 MAPK-JNK-dependent pathways via a GLP1 receptor-dependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Erdogdu

Eriksson

et al. 2013

Journal of Molecular Endocrinology

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“…Forty-eight hours after transduction, cells were then treated with or without of TNF-α (20 ng/mL) for another 24 hr. Cell extracts prepared from HUVECs were analyzed by western blotting as previously described 1,2 . Briefly, cells were rinsed with ice-cold PBS (pH 7.4) and lysed with lysis buffer containing: 50.0 mmol/L Tris pH=7.6, 150.0 mmol/L NaCl, 0.1% SDS, 1.0% NP-40, Protease Inhibitor Cocktail, Phosphatase Inhibitor Cocktail (Sigma, St. Louis, MO, USA)).…”

Section: Western Blottingmentioning

confidence: 99%

“…1 Dysregulation of NO synthesis attributable to the abnormal activity or expression of eNOS or both has been considered to be a major contributor to the pathogenesis of vascular diseases, such as hypertension and atherosclerosis. 2,3 eNOS expression can be modulated by a variety of physiological and pathophysiological stimuli.…”

mentioning

confidence: 99%

Essential Role of MicroRNA-155 in Regulating Endothelium-Dependent Vasorelaxation by Targeting Endothelial Nitric Oxide Synthase

Sun¹,

Zeng²,

Li³

et al. 2012

Hypertension

285

229

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Abstract-Nitric oxide generated by endothelial nitric oxide synthase (eNOS) plays an important role in maintaining cardiovascular homeostasis. Under various pathological conditions, abnormal expression of eNOS contributes to endothelial dysfunction and the development of cardiovascular diseases. A variety of pathological stimuli has been reported to decrease eNOS expression mainly through decreasing eNOS mRNA stability by regulating the binding of several cytosolic proteins to the cis-acting sequences within eNOS mRNA 3′ untranslated regions. However, the detailed mechanisms remain elusive. Because microRNAs inhibit gene expression through binding to the 3′ untranslated regions of their target mRNAs, microRNAs may be the important posttranscriptional modulators of eNOS expression. Here, we provided evidence that eNOS is a direct target of miR-155. Overexpression of miR-155 decreased, whereas inhibition of miR-155 increased, eNOS expression and NO production in human umbilical vein endothelial cells and acetylcholineinduced endothelium-dependent vasorelaxation in human internal mammary arteries. Inflammatory cytokines including tumor necrosis factor-α increased miR-155 expression. Inhibition of miR-155 reversed tumor necrosis factor-α-induced downregulation of eNOS expression and impairment of endothelium-dependent vasorelaxation. Moreover, we observed that simvastatin attenuated tumor necrosis factor-α-induced upregulation of miR-155 and ameliorated the effects of tumor necrosis factor-α on eNOS expression and endothelium-dependent vasodilation. Simvastatin decreased miR-155 expression through interfering mevalonate-geranylgeranyl-pyrophosphate-RhoA signaling pathway. These findings indicated that miR-155 is an essential regulator of eNOS expression and endothelium-dependent vasorelaxation.Inhibition of miR-155 may be a new therapeutic approach to improve endothelial dysfunction during the development of cardiovascular diseases.

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“…nNOS regulates calcium handling in the heart through the voltage-dependent calcium channels [6]. In the beta cell, exocytosis of insulin granules is triggered by an influx of calcium through these calcium channels [7].…”

mentioning

confidence: 99%

Genetic variation in the NOS1AP gene is associated with the incidence of diabetes mellitus in users of calcium channel blockers

Becker¹,

Visser²,

Newton‐Cheh

et al. 2008

Diabetologia

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Recent advances in the understanding of the role of nitric oxide in cardiovascular homeostasis

Cited by 131 publications

References 411 publications

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways

Essential Role of MicroRNA-155 in Regulating Endothelium-Dependent Vasorelaxation by Targeting Endothelial Nitric Oxide Synthase

Genetic variation in the NOS1AP gene is associated with the incidence of diabetes mellitus in users of calcium channel blockers

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