Activation of Vascular Protein Kinase C-β Inhibits Akt-Dependent Endothelial Nitric Oxide Synthase Function in Obesity-Associated Insulin Resistance

Naruse, Keiko; Rask‐Madsen, Christian; Takahara, Noriko; Ha, Sung-Woo; Suzuma, Kiyoshi; Way, Kerrie J.; Jacobs, Judith R.C.; Clermont, Allen C.; Ueki, Kohjiro; Ohshiro, Yuzuru; Zhang, Junqing; Goldfine, Allison B.; King, George L.

doi:10.2337/diabetes.55.03.06.db05-0771

Cited by 178 publications

(169 citation statements)

References 30 publications

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“…It had been previously noted that PMA-induced ACE expression is dependent on the transcription factor activating protein-1 (AP-1) [9], of which c-Fos is a constituent. A physiopathological example of ACE upregulation by such conditions may be the prediabetic state in Zucker rats where diacylglycerol, the endogenous PKC stimulant, is increased in vascular tissue, as well as the expression of several PKC isoforms [24]. This may explain the high ACE activity and low BK half-life in membranes isolated from young, prediabetic Zucker rats relative to Sprague-Dawley rats [1], and may deprive diabetic individuals from the postulated protective effects of low kinin levels in tissues.…”

Section: Pharmacological Modulators Of Ace Expression In Huvecs: Dynamentioning

confidence: 99%

A ligand-based approach to investigate the expression and function of angiotensin converting enzyme in intact human umbilical vein endothelial cells

et al. 2010

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Section: Pharmacological Modulators Of Ace Expression In Huvecs: Dynamentioning

confidence: 99%

A ligand-based approach to investigate the expression and function of angiotensin converting enzyme in intact human umbilical vein endothelial cells

et al. 2010

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“…Of note, endothelial PKCβ activation has been suggested to negatively impact endothelial function and to inhibit eNOSactivating pathways (45)(46)(47)(48).…”

Section: Figurementioning

confidence: 99%

Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease

Besler¹,

Heinrich²,

Rohrer³

et al. 2011

J. Clin. Invest.

488

446

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Therapies that raise levels of HDL, which is thought to exert atheroprotective effects via effects on endothelium, are being examined for the treatment or prevention of coronary artery disease (CAD). However, the endothelial effects of HDL are highly heterogeneous, and the impact of HDL of patients with CAD on the activation of endothelial eNOS and eNOS-dependent pathways is unknown. Here we have demonstrated that, in contrast to HDL from healthy subjects, HDL from patients with stable CAD or an acute coronary syndrome (HDL CAD ) does not have endothelial antiinflammatory effects and does not stimulate endothelial repair because it fails to induce endothelial NO production. Mechanistically, this was because HDL CAD activated endothelial lectin-like oxidized LDL receptor 1 (LOX-1), triggering endothelial PKCβII activation, which in turn inhibited eNOS-activating pathways and eNOS-dependent NO production. We then identified reduced HDL-associated paraoxonase 1 (PON1) activity as one molecular mechanism leading to the generation of HDL with endothelial PKCβII-activating properties, at least in part due to increased formation of malondialdehyde in HDL. Taken together, our data indicate that in patients with CAD, HDL gains endothelial LOX-1-and thereby PKCβII-activating properties due to reduced HDL-associated PON1 activity, and that this leads to inhibition of eNOS-activation and the subsequent loss of the endothelial antiinflammatory and endothelial repair-stimulating effects of HDL.

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“…Furthermore, VEGF itself has effects on the phosphorylation of eNOS through this same pathway. 33 However, the level of expression of eNOS protein under diabetic conditions is still controversial. As it was in our study, it has been reported that eNOS protein expression is decreased in human coronary artery endothelial cells under hyperglycemic conditions, 34 although other studies have reported an increase or no change in eNOS protein expression.…”

mentioning

confidence: 99%

Inhibition of Protein Kinase C β Ameliorates Impaired Angiogenesis in Type I Diabetic Mice Complicating Myocardial Infarction

Ikeda

Matsushita

Sakakibara

2012

Circ J

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Activation of Vascular Protein Kinase C-β Inhibits Akt-Dependent Endothelial Nitric Oxide Synthase Function in Obesity-Associated Insulin Resistance

Cited by 178 publications

References 30 publications

A ligand-based approach to investigate the expression and function of angiotensin converting enzyme in intact human umbilical vein endothelial cells

A ligand-based approach to investigate the expression and function of angiotensin converting enzyme in intact human umbilical vein endothelial cells

Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease

Inhibition of Protein Kinase C β Ameliorates Impaired Angiogenesis in Type I Diabetic Mice Complicating Myocardial Infarction

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