Adipocytes Produce Aldosterone Through Calcineurin-Dependent Signaling Pathways Implications in Diabetes Mellitus-Associated Obesity and Vascular Dysfunction
Adipocytes Produce Aldosterone Through Calcineurin-Dependent Signaling Pathways Implications in Diabetes Mellitus-Associated Obesity and Vascular Dysfunction
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DOI：
10.1161/hypertensionaha.111.190223
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发表时间：
2012-05-01
期刊：
影响因子：
8.3
通讯作者：
Touyz, Rhian M.
中科院分区：
文献类型：
--
作者：
Briones, Ana M.;Cat, Aurelie Nguyen Dinh;Touyz, Rhian M.
我们报道了醛固酮作为一种新的脂肪细胞衍生因子调节血管功能。我们的目的是研究脂肪细胞源性醛固酮的分子机制，信号通路和功能意义，并测试是否脂肪细胞源性醛固酮增加糖尿病相关的肥胖，这有助于血管功能障碍。在3 T3-L1脂肪细胞系和从人和小鼠（C57 BL/6 J）脂肪组织分离的成熟脂肪细胞中进行研究。从肥胖糖尿病db/db和对照db/+小鼠获得具有和不具有血管周围脂肪和成熟脂肪细胞的肠系膜动脉。在3 T3-L1和成熟脂肪细胞中检测到醛固酮合成酶（CYP 11B 2; mRNA和蛋白），其基础分泌醛固酮并响应于血管紧张素II（Ang II）。在3 T3-L1脂肪细胞中，Ang II刺激增加醛固酮分泌和CYP 11B 2表达。血管紧张素II的作用被血管紧张素II 1型受体拮抗剂（坎地沙坦）和钙调磷酸酶抑制剂（环孢素A和FK 506）和活化T细胞核因子（VIVIT）减弱。FAD 286（醛固酮合成酶抑制剂）钝化脂肪细胞分化。在坎地沙坦治疗的db/db小鼠（1 mg/kg/天，4周）中，血浆醛固酮增加，CYP 11B 2表达和醛固酮分泌减少。乙酰胆碱诱导的舒张db/db肠系膜动脉含有血管周围脂肪改善依普利酮（盐皮质激素受体拮抗剂）没有影响db/+小鼠。脂肪细胞具有醛固酮合成酶，并以Ang II/Ang II 1型受体/钙调神经磷酸酶/活化T细胞核因子依赖性方式产生醛固酮。功能性脂肪细胞衍生的醛固酮分别以自分泌和旁分泌方式调节脂肪细胞分化和血管功能。这些新的发现将脂肪细胞确定为糖尿病相关肥胖中醛固酮和血管功能障碍之间的假定联系。
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.