Periadventitial adipose tissue impairs coronary endothelial function via PKC-β-dependent phosphorylation of nitric oxide synthase

Payne, Gregory A.; Bohlen, H. G.; Dinçer, Ü. Deniz; Borbouse, Léna; Tune, Johnathan D.

doi:10.1152/ajpheart.00116.2009

Cited by 76 publications

(73 citation statements)

References 53 publications

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“…The other possibility is the direct influence of an enlarged perivascular fat mass on vessel wall dysfunction, as suggested in obesity and type 2 diabetes, 11 in heart disease animal models, 39 and more specifically in the modulation of coronary endothelial function. 8,9 Inflammation, vasoactive adipokines, and mediators secreted locally by IPF could explain our findings. In fact, enlarged adipocytes increase the proportion of macrophages, T lymphocytes, 10 and detrimental adipocytokines, such as leptin, resistin, interleukin 6, and tumor necrosis factor ␣.…”

Section: Discussionmentioning

confidence: 72%

“…18 -20 The relationship between accumulation of IPF and EPF and myocardial perfusion (MBF) in patients with CAD has not been investigated, although a strong mechanistic link is supported by evidence of vasoactive adipokines released into the coronary lumen. 8,9,21 One group 22 has examined and found a correlation between echocardiographically measured CFR and epicardial fat thickness in women with normal coronary arteries.…”

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confidence: 99%

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Intrapericardial, But Not Extrapericardial, Fat Is an Independent Predictor of Impaired Hyperemic Coronary Perfusion in Coronary Artery Disease

Bucci

Joutsiniemi

Saraste

et al. 2011

ATVB

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Objective-To measure intrapericardial fat (IPF), extrapericardial fat (EPF), and myocardial perfusion (MBF) in patients with and without coronary artery disease (CAD), hypothesizing that perfusion is more strongly associated with IPF because it is in direct anatomic contiguity with the myocardium or coronary arteries. Methods and Results-Fat surrounding the heart may increase the risk of CAD and calcification, but little is known about the role of MBF in this relationship. The study included 107 patients with an intermediate likelihood of CAD. Positron emission tomography/computed tomography was used to measure IPF and EPF volumes and coronary artery calcium level, together with MBF at rest and during adenosine-induced hyperemia. Subsequently, all subjects underwent coronary angiography and were grouped for presence/absence of CAD and severity of myocardial hypoperfusion. IPF and EPF levels were higher in men and in patients with CAD (nϭ85) than in those without CAD (nϭ22) (PϽ0.001). EPF was increased regardless of the degree of stenoses (nϭ45), whereas IPF was selectively increased in subjects with obstructive stenoses (nϭ40

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Section: Discussionmentioning

confidence: 72%

mentioning

confidence: 99%

Intrapericardial, But Not Extrapericardial, Fat Is an Independent Predictor of Impaired Hyperemic Coronary Perfusion in Coronary Artery Disease

Bucci

Joutsiniemi

Saraste

et al. 2011

ATVB

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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%

“…Our findings further indicated that increased endothelial PKCβII activation by HDL CAD was involved in the impaired effects of HDL CAD on eNOS-derived NO production and was mediated, at least in part, via the endothelial LOX-1 receptor. Endothelial PKCβ activation has been observed to promote endothelial dysfunction, to inhibit Akt-dependent eNOS-activating phosphorylation at Ser1177, to increase eNOS-inhibiting phosphorylation at Thr495 (45)(46)(47)(48)58), and to promote endothelial inflammatory activation (49).…”

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.

493

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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“…4,5, 7 In contrast, PVAT may enhance vascular contractile responses by preventing endothelium-dependent vasodilatation through inhibition of endothelial nitric oxide synthase. 8 Furthermore, PVAT increases the extent of vasoconstriction via generation of contractile superoxide anions, which are released after electric field stimulation from functional reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase in rat mesenteric arteries. 9 Lipoatrophic mice born without white fat tissue have a markedly decreased amount of PVAT accompanied with increased arterial pressure and compromised vascular function.…”

mentioning

confidence: 99%

Periadventitial Adipose Tissue Promotes Endothelial Dysfunction via Oxidative Stress in Diet-Induced Obese C57Bl/6 Mice

Ketonen

Shi

Martonen

et al. 2010

Circ J

186

168

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Background: Biological substances derived from perivascular fat modulate vascular tone, thus alterations in periadventitial adipose tissue (PVAT) may aggravate endothelial dysfunction in obesity. Methods and Results:Male C57Bl/6 mice were fed either a high-fat diet or standard laboratory chow for 8 months. Vascular responses were studied in organ bath chambers from abdominal aortic ring preparations in the absence or presence of PVAT. The amount of PVAT as well as the cross-sectional area of adipocytes were increased in obese mice. In the presence of PVAT, obese aortas displayed impaired endothelium-dependent vasodilation whereas endothelium-independent vasodilatation was unaltered. Endothelium-dependent vasodilatation was restored after removal of PVAT and after reducing superoxide and hydrogen peroxide formation in the vascular wall by Tiron or polyethylene-glycol-catalase, respectively. PVAT from obese mice showed increased formation of hydrogen peroxide and superoxide. The PVAT-derived oxidative stress was abolished by pretreatment with the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase inhibitor, apocynin. The anti-contractile function of PVAT found in lean mice was completely abolished in obese mice, but partially restored after pretreatment with Tiron. The mRNA expressions of monocyte chemotactic protein-1, leptin and NADPH oxidase were markedly higher in the PVAT of obese than lean mice. Conclusions:PVAT promotes endothelial dysfunction in diet-induced obese C57Bl/6 mice via mechanisms that are linked to increased NADPH oxidase-derived oxidative stress and increased production of pro-inflammatory cytokines. (Circ J 2010; 74: 1479 - 1487

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Periadventitial adipose tissue impairs coronary endothelial function via PKC-β-dependent phosphorylation of nitric oxide synthase

Cited by 76 publications

References 53 publications

Intrapericardial, But Not Extrapericardial, Fat Is an Independent Predictor of Impaired Hyperemic Coronary Perfusion in Coronary Artery Disease

Intrapericardial, But Not Extrapericardial, Fat Is an Independent Predictor of Impaired Hyperemic Coronary Perfusion in Coronary Artery Disease

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

Periadventitial Adipose Tissue Promotes Endothelial Dysfunction via Oxidative Stress in Diet-Induced Obese C57Bl/6 Mice

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