Regulation of G-protein alpha i2 subunit expression by oxidized low-density lipoprotein.

Liao, James K.; Clark, Stephen L.

doi:10.1172/jci117816

Cited by 69 publications

(33 citation statements)

References 40 publications

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“…23 The higher intracellular levels of oxy-LDL in turn inactivate G i proteins and their ability to enhance the release of NO. 45,46 This interpretation implies that the augmented presence of A-FABP precedes the increase in oxidative stress causing the selective dysfunction in regenerated endothelial cells. The observations that BMS309403 potentiates, while apocynin only protects the response to the monoamine in preparations with regenerated endothelium favors the primary importance of A-FABP in causing the selective dysfunction of the G i proteins.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

A-FABP and Oxidative Stress Underlie the Impairment of Endothelium-Dependent Relaxations to Serotonin and the Intima-Medial Thickening in the Porcine Coronary Artery with Regenerated Endothelium

Chan

Zhao²,

Liao³

et al. 2012

ACS Chem. Neurosci.

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Experiments were designed to determine the cause of the selective dysfunction of G i proteins, characterized by a reduced endothelium-dependent relaxation to serotonin (5-hydroxytryptamine), in coronary arteries lined with regenerated endothelial cells. Part of the endothelium of the left anterior descending coronary artery of female pigs was removed in vivo to induce regeneration. The animals were treated chronically with vehicle (control), apocynin (antioxidant), or BMS309403 (A-FABP inhibitor) for 28 days before functional examination and histological analysis of segments of coronary arteries with native or regenerated endothelium of the same hearts. Isometric tension was recorded in organ chambers and cumulative concentrationrelaxation curves obtained in response to endothelium-dependent [serotonin (G i protein mediated activation of eNOS) and bradykinin (G q protein mediated activation of eNOS)] and independent [detaNONOate (cGMP-mediated), isoproterenol (cAMP-mediated)] vasodilators. The two inhibitors tested did not acutely affect relaxations of preparations with either native or regenerated endothelium. In the chronically treated groups, however, both apocynin and BMS309403 abolished the reduction in relaxation to serotonin in segments covered with regenerated endothelium and prevented the intima-medial thickening caused by endothelial regeneration, without affecting responses to bradykinin or endothelium-independent agonists (detaNONOate and isoproterenol). Thus, inhibition of either oxidative stress or A-FABP likely prevents both the selective dysfunction of G i protein mediated relaxation to serotonin and the neointimal thickening resulting from endothelial regeneration.

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Section: ■ Results and Discussionmentioning

confidence: 99%

A-FABP and Oxidative Stress Underlie the Impairment of Endothelium-Dependent Relaxations to Serotonin and the Intima-Medial Thickening in the Porcine Coronary Artery with Regenerated Endothelium

Chan

Zhao²,

Liao³

et al. 2012

ACS Chem. Neurosci.

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“…In this study, NO detection was performed in the presence of an excess of superoxide dismutase, thereby excluding the oxidative stress as a potential cause of the impairment in NO production by HC serum-treated cells in our experimental conditions. Aside from the inactivation of NO by reactive oxygen species, several studies examined the relationship between dyslipidemia and endothelial dysfunction through a direct modulation of eNOS expression and/or activation; they identified defects in the coupling of the receptor-G protein interaction leading to eNOS stimulation (6,36) and effects of oxidized LDL (oxLDL) on the steady-state mRNA levels of the enzyme (13,14). In the present study, these mechanisms are unlikely to account for the impairment in eNOS activity observed in endothelial cells exposed to HC serum or to high concentrations of isolated LDL.…”

Section: Discussionmentioning

confidence: 99%

Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase

Féron¹,

Dessy²,

Moniotte³

et al. 1999

J. Clin. Invest.

372

234

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Hypercholesterolemia is a central pathogenic factor of endothelial dysfunction caused in part by an impairment of endothelial nitric oxide (NO) production through mechanisms that remain poorly characterized. The activity of the endothelial isoform of NO synthase (eNOS) was recently shown to be modulated by its reciprocal interactions with the stimulatory Ca 2+ -calmodulin complex and the inhibitory protein caveolin. We examined whether hypercholesterolemia may reduce NO production through alteration of this regulatory equilibrium. Bovine aortic endothelial cells were cultured in the presence of serum obtained from normocholesterolemic (NC) or hypercholesterolemic (HC) human volunteers. Exposure of endothelial cells to the HC serum upregulated caveolin abundance without any measurable effect on eNOS protein levels. This effect of HC serum was associated with an impairment of basal NO release paralleled by an increase in inhibitory caveolin-eNOS complex formation. Similar treatment with HC serum significantly attenuated the NO production stimulated by the calcium ionophore A23187. Accordingly, higher calmodulin levels were required to disrupt the enhanced caveolin-eNOS heterocomplex from HC serum-treated cells. Finally, cell exposure to the low-density lipoprotein (LDL) fraction alone dose-dependently reproduced the inhibition of basal and stimulated NO release, as well as the upregulation of caveolin expression and its heterocomplex formation with eNOS, which were unaffected by cotreatment with antioxidants. Together, our data establish a new mechanism for the cholesterol-induced impairment of NO production through the modulation of caveolin abundance in endothelial cells, a mechanism that may participate in the pathogenesis of endothelial dysfunction and the proatherogenic effects of hypercholesterolemia.

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“…Nuclei from EC (4 x 107 cells) exposed to the indicated 02 concentration from 12 h were isolated as described previously (18). In vitro transcription was carried out in a shaking water bath at 30°C for 30 min in a buffer containing 10 to NOS, pGEM, and ,3-tubulin were vacuum-transferred onto nylon membranes using a slot blot apparatus (Schleicher and Schuell).…”

Section: Methodsmentioning

confidence: 99%

Regulation of bovine endothelial constitutive nitric oxide synthase by oxygen.

Liao¹,

Zulueta²,

Yu³

et al. 1995

J. Clin. Invest.

Self Cite

190

133

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Oxygen (02) may regulate pulmonary vascular resistance through changes in endothelial nitric oxide (NO) production. To determine whether constitutive NO synthase (cNOS) is regulated by 02, we assessed cNOS expression and activity in bovine pulmonary artery endothelial cells exposed to different concentrations of 02-In a time-dependent manner, changes in 02 concentration from 95 to 3% produced a progressive decrease in cNOS mRNA and protein levels resulting in 4.8-and 43-fold reductions after 24 h, respectively. This correlated with changes in cNOS activity as determined by nitrite measurements. Compared with 20% 02, cNOS activity was increased 1.5-fold in 95% 02 and decreased 1.9-fold in 3% 02. A decrease in 02 concentration from 95 to 3% shortened cNOS mRNA half-life from 46 to 24 h and caused a 20-fold repression of cNOS gene transcription. Treatment with cycloheximide produced a threefold increase in cNOS mRNA at all 02 concentrations, suggesting that cNOS mRNA expression is negatively regulated under basal condition. We conclude that 02 upregulates cNOS expression through transcriptional and posttranscriptional mechanisms. A decrease in cNOS activity in the presence of low 02 levels, therefore, may contribute to hypoxia-induced vasoconstriction in the pulmonary circulation. (J. Clin. Invest. 1995Invest. . 96:2661Invest. -2666

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Regulation of G-protein alpha i2 subunit expression by oxidized low-density lipoprotein.

Abstract: Oxidized low-density lipoprotein (LDL) inhibits signalling pathways mediated by pertussis toxin-sensitive guanine nucleotide-binding proteins (GI proteins

Cited by 69 publications

References 40 publications

A-FABP and Oxidative Stress Underlie the Impairment of Endothelium-Dependent Relaxations to Serotonin and the Intima-Medial Thickening in the Porcine Coronary Artery with Regenerated Endothelium

A-FABP and Oxidative Stress Underlie the Impairment of Endothelium-Dependent Relaxations to Serotonin and the Intima-Medial Thickening in the Porcine Coronary Artery with Regenerated Endothelium

Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase

Regulation of bovine endothelial constitutive nitric oxide synthase by oxygen.

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