Kidney Research Centre, Ottawa Hospital Research Institute, and Division of Nephrology, University of Ottawa, Ottawa, Ontario, Canada.
Hypertension. 2012 May;59(5):1069-78. doi: 10.1161/HYPERTENSIONAHA.111.190223. Epub 2012 Apr 9.
We reported aldosterone as a novel adipocyte-derived factor that regulates vascular function. We aimed to investigate molecular mechanisms, signaling pathways, and functional significance of adipocyte-derived aldosterone and to test whether adipocyte-derived aldosterone is increased in diabetes mellitus-associated obesity, which contributes to vascular dysfunction. Studies were performed in the 3T3-L1 adipocyte cell line and mature adipocytes isolated from human and mouse (C57BL/6J) adipose tissue. Mesenteric arteries with and without perivascular fat and mature adipocytes were obtained from obese diabetic db/db and control db/+ mice. Aldosterone synthase (CYP11B2; mRNA and protein) was detected in 3T3-L1 and mature adipocytes, which secrete aldosterone basally and in response to angiotensin II (Ang II). In 3T3-L1 adipocytes, Ang II stimulation increased aldosterone secretion and CYP11B2 expression. Ang II effects were blunted by an Ang II type 1 receptor antagonist (candesartan) and inhibitors of calcineurin (cyclosporine A and FK506) and nuclear factor of activated T-cells (VIVIT). FAD286 (aldosterone synthase inhibitor) blunted adipocyte differentiation. In candesartan-treated db/db mice (1 mg/kg per day, 4 weeks) increased plasma aldosterone, CYP11B2 expression, and aldosterone secretion were reduced. Acetylcholine-induced relaxation in db/db mesenteric arteries containing perivascular fat was improved by eplerenone (mineralocorticoid receptor antagonist) without effect in db/+ mice. Adipocytes possess aldosterone synthase and produce aldosterone in an Ang II/Ang II type 1 receptor/calcineurin/nuclear factor of activated T-cells-dependent manner. Functionally adipocyte-derived aldosterone regulates adipocyte differentiation and vascular function in an autocrine and paracrine manner, respectively. These novel findings identify adipocytes as a putative link between aldosterone and vascular dysfunction in diabetes mellitus-associated obesity.
我们报道了醛固酮作为一种调节血管功能的新型脂肪细胞衍生因子。我们旨在研究脂肪细胞衍生醛固酮的分子机制、信号通路和功能意义，并测试其在糖尿病相关肥胖症中是否增加，从而导致血管功能障碍。这些研究是在 3T3-L1 脂肪细胞系和从人及小鼠（C57BL/6J）脂肪组织分离的成熟脂肪细胞中进行的。从肥胖的糖尿病 db/db 和对照 db/+小鼠中获得了带有和不带有血管周围脂肪的肠系膜动脉和成熟脂肪细胞。醛固酮合酶（CYP11B2；mRNA 和蛋白）在 3T3-L1 和成熟脂肪细胞中被检测到，它们基础分泌醛固酮，并对血管紧张素 II（Ang II）有反应。在 3T3-L1 脂肪细胞中，Ang II 刺激增加了醛固酮的分泌和 CYP11B2 的表达。Ang II 的作用被 Ang II 型 1 受体拮抗剂（坎地沙坦）和钙调神经磷酸酶抑制剂（环孢菌素 A 和 FK506）及活化 T 细胞核因子（VIVIT）所阻断。FAD286（醛固酮合酶抑制剂）阻断了脂肪细胞分化。在坎地沙坦治疗的 db/db 小鼠（每天 1 毫克/千克，持续 4 周）中，血浆醛固酮、CYP11B2 表达和醛固酮分泌增加，而在 db/+小鼠中则没有效果。Eplerenone（盐皮质激素受体拮抗剂）改善了含有血管周围脂肪的 db/db 肠系膜动脉中乙酰胆碱诱导的舒张作用，而在 db/+小鼠中则没有效果。脂肪细胞具有醛固酮合酶，并以血管紧张素 II/血管紧张素 II 型 1 受体/钙调神经磷酸酶/活化 T 细胞核因子依赖的方式产生醛固酮。功能性脂肪细胞衍生的醛固酮分别以自分泌和旁分泌的方式调节脂肪细胞分化和血管功能。这些新发现确定了脂肪细胞作为糖尿病相关肥胖症中醛固酮与血管功能障碍之间的潜在联系。
