Ottawa Hospital Research Institute/University of Ottawa, 451 Smyth Rd, Ottawa, K1H 8M5 Ontario, Canada.
Hypertension. 2011 Sep;58(3):479-88. doi: 10.1161/HYPERTENSIONAHA.110.168872. Epub 2011 Jul 25.
Adipose tissue influences vascular function through adipocyte-derived factors, including components of the renin-angiotensin-aldosterone system. Molecular mechanisms underlying these phenomena are elusive. We investigated the role of adipocyte-derived factors on mitogen-activated protein kinases (MAPKs), proinflammatory status, apoptosis, and mitogenic signaling in vascular smooth muscle cells (VSMCs) and questioned whether these effects involve mineralocorticoid receptor (MR), glucocorticoid receptor (GR), and angiotensin II type 1 receptor (AT(1)R). Cultured mouse VSMCs were exposed to adipocyte-conditioned medium (ACM) from differentiated 3T3-L1 adipocytes. ACM induced phosphorylation of stress-activated protein kinase/c-Jun N-terminal kinase, p38MAPK, and extracellular signal-regulated kinase 1/2 and increased expression of proinflammatory and proliferative markers in VSMCs. Eplerenone (MR antagonist), mifepristone (GR antagonist), and candesartan (AT(1)R antagonist) inhibited ACM-induced effects on extracellular signal-regulated kinase 1/2, p38MAPK, and proliferating cell nuclear antigen, without influencing apoptosis (Bax, Bcl, and caspase 3). Stress-activated protein kinase/c-Jun N-terminal kinase phosphorylation was inhibited by mifepristone and candesartan but not by eplerenone. ACM-induced increase of fibronectin, vascular cell adhesion molecule 1, and plasminogen activator inhibitor 1 expression was blocked by MR and AT(1)R antagonism but not by GR inhibition. ACM has no effect on GR, MR, and AT(1)R expression. Our data show that adipocyte-derived factors influence MAPK signaling, leading to VSMC proinflammatory and profibrotic responses through distinct pathways. Although ACM stimulates p38MAPK and extracellular signal-regulated kinase 1/2 phosphorylation through MR, GR, and AT(1)R, activation of stress-activated protein kinase/c-Jun N-terminal kinase involves GR and AT(1)R. These findings suggest that adipocyte-derived factors regulate VSMC function through specific MAPKs linked to MR, GR, and AT(1)R, a posttranslational phenomenon, because ACM did not influence receptor expression. Such cross-talk between adipocytes and VSMCs may provide a potential molecular mechanism linking renin-angiotensin-aldosterone system, adipocytes, and vascular function.
脂肪组织通过脂肪细胞衍生因子影响血管功能，包括肾素-血管紧张素-醛固酮系统的成分。这些现象的潜在分子机制尚不清楚。我们研究了脂肪细胞衍生因子对血管平滑肌细胞（VSMC）中丝裂原激活蛋白激酶（MAPK）、促炎状态、细胞凋亡和有丝分裂信号的作用，并质疑这些作用是否涉及盐皮质激素受体（MR）、糖皮质激素受体（GR）和血管紧张素 II 型 1 受体（AT（1）R）。培养的小鼠 VSMC 暴露于分化的 3T3-L1 脂肪细胞的脂肪细胞条件培养基（ACM）中。ACM 诱导应激激活蛋白激酶/c-Jun N-末端激酶、p38MAPK 和细胞外信号调节激酶 1/2 的磷酸化，并增加 VSMC 中促炎和增殖标记物的表达。依普利酮（MR 拮抗剂）、米非司酮（GR 拮抗剂）和坎地沙坦（AT（1）R 拮抗剂）抑制 ACM 诱导的细胞外信号调节激酶 1/2、p38MAPK 和增殖细胞核抗原的作用，而不影响细胞凋亡（Bax、Bcl 和 caspase 3）。应激激活蛋白激酶/c-Jun N-末端激酶的磷酸化被米非司酮和坎地沙坦抑制，但不受依普利酮影响。ACM 诱导的纤连蛋白、血管细胞粘附分子 1 和纤溶酶原激活物抑制剂 1 表达增加被 MR 和 AT（1）R 拮抗作用阻断，但不受 GR 抑制作用阻断。ACM 对 GR、MR 和 AT（1）R 的表达没有影响。我们的数据表明，脂肪细胞衍生因子影响 MAPK 信号，通过不同的途径导致 VSMC 促炎和促纤维化反应。尽管 ACM 通过 MR、GR 和 AT（1）R 刺激 p38MAPK 和细胞外信号调节激酶 1/2 的磷酸化，但应激激活蛋白激酶/c-Jun N-末端激酶的激活涉及 GR 和 AT（1）R。这些发现表明，脂肪细胞衍生因子通过与 MR、GR 和 AT（1）R 相关的特定 MAPK 调节 VSMC 功能，这是一种翻译后现象，因为 ACM 不影响受体表达。脂肪细胞和 VSMC 之间的这种串扰可能为连接肾素-血管紧张素-醛固酮系统、脂肪细胞和血管功能的潜在分子机制提供了依据。
