Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Circulation. 2013 Jun 4;127(22):2209-21. doi: 10.1161/CIRCULATIONAHA.112.001133. Epub 2013 Apr 26.
Adiponectin is an adipokine with potentially important roles in human cardiovascular disease states. We studied the role of adiponectin in the cross-talk between adipose tissue and vascular redox state in patients with atherosclerosis.
The study included 677 patients undergoing coronary artery bypass graft surgery. Endothelial function was evaluated by flow-mediated dilation of the brachial artery in vivo and by vasomotor studies in saphenous vein segments ex vivo. Vascular superoxide (O2(-)) and endothelial nitric oxide synthase (eNOS) uncoupling were quantified in saphenous vein and internal mammary artery segments. Local adiponectin gene expression and ex vivo release were quantified in perivascular (saphenous vein and internal mammary artery) subcutaneous and mesothoracic adipose tissue from 248 patients. Circulating adiponectin was independently associated with nitric oxide bioavailability and O2(-) production/eNOS uncoupling in both arteries and veins. These findings were supported by a similar association between functional polymorphisms in the adiponectin gene and vascular redox state. In contrast, local adiponectin gene expression/release in perivascular adipose tissue was positively correlated with O2(-) and eNOS uncoupling in the underlying vessels. In ex vivo experiments with human saphenous veins and internal mammary arteries, adiponectin induced Akt-mediated eNOS phosphorylation and increased tetrahydrobiopterin bioavailability, improving eNOS coupling. In ex vivo experiments with human saphenous veins/internal mammary arteries and adipose tissue, we demonstrated that peroxidation products produced in the vascular wall (ie, 4-hydroxynonenal) upregulate adiponectin gene expression in perivascular adipose tissue via a peroxisome proliferator-activated receptor-γ-dependent mechanism.
We demonstrate for the first time that adiponectin improves the redox state in human vessels by restoring eNOS coupling, and we identify a novel role of vascular oxidative stress in the regulation of adiponectin expression in human perivascular adipose tissue.
脂联素是一种脂肪细胞因子，在人类心血管疾病状态中可能具有重要作用。我们研究了脂联素在动脉粥样硬化患者脂肪组织与血管氧化还原状态相互作用中的作用。
该研究纳入了 677 例行冠状动脉旁路移植术的患者。通过体内肱动脉血流介导的扩张和离体隐静脉和内乳动脉段的血管舒缩研究评估内皮功能。定量检测隐静脉和内乳动脉段的血管超氧阴离子（O2(-)）和内皮型一氧化氮合酶（eNOS）解偶联。对 248 例患者的血管周围（隐静脉和内乳动脉）皮下和中胸脂肪组织中的局部脂联素基因表达和离体释放进行定量。循环脂联素与两种动脉和静脉中的一氧化氮生物利用度和 O2(-)产生/eNOS 解偶联独立相关。这些发现得到了脂联素基因功能多态性与血管氧化还原状态之间相似关联的支持。相比之下，血管周围脂肪组织中的局部脂联素基因表达/释放与潜在血管中的 O2(-)和 eNOS 解偶联呈正相关。在人隐静脉和内乳动脉的离体实验中，脂联素诱导 Akt 介导的 eNOS 磷酸化并增加四氢生物蝶呤的生物利用度，改善 eNOS 偶联。在人隐静脉/内乳动脉和脂肪组织的离体实验中，我们证明血管壁中产生的过氧化产物（即 4-羟基壬烯醛）通过过氧化物酶体增殖物激活受体-γ依赖性机制上调血管周围脂肪组织中的脂联素基因表达。
我们首次证明，脂联素通过恢复 eNOS 偶联来改善人体血管的氧化还原状态，并确定血管氧化应激在调节人体血管周围脂肪组织中脂联素表达方面的新作用。
