Adipocyte-Specific Mineralocorticoid Receptor Overexpression in Mice Is Associated With Metabolic Syndrome and Vascular Dysfunction: Role of Redox-Sensitive PKG-1 and Rho Kinase
Adipocyte-Specific Mineralocorticoid Receptor Overexpression in Mice Is Associated With Metabolic Syndrome and Vascular Dysfunction: Role of Redox-Sensitive PKG-1 and Rho Kinase
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DOI：
10.2337/db15-1627
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发表时间：
2016-08-01
期刊：
影响因子：
7.7
通讯作者：
Touyz, Rhian M.
中科院分区：
文献类型：
--
作者：
Cat, Aurelie Nguyen Dinh;Antunes, Tayze T.;Touyz, Rhian M.
矿化皮质激素受体（MR）在肥胖个体和动物的脂肪组织中表达增加。我们之前已经证明，小鼠脂肪细胞- mr过表达（Adipo-MROE）与代谢变化有关。脂肪细胞MR是否直接影响这些小鼠的血管功能尚不清楚。我们在Adipo-MROE小鼠的耐药肠系膜动脉和培养的脂肪细胞中验证了这一假设。探讨了血管/血管平滑肌细胞和脂肪组织/脂肪细胞的分子机制，重点关注氧化还原敏感途径、Rho激酶活性和蛋白激酶G型-1 （PKG-1）信号传导。与对照mr小鼠相比，脂肪- mroe小鼠表现出血管收缩性降低，这与脂肪细胞衍生的过氧化氢生成增加、血管氧化还原敏感的PKG-1激活以及Rho激酶活性下调有关。与这些血管变化相关的是脂肪- mroe中弹性蛋白含量的增加。Rp-8-Br-PET-cGMPS抑制PKG-1在Adipo-MROE中正常化血管收缩。在脂肪细胞条件培养基存在的情况下，脂肪组织的抗收缩作用在Adipo-MROE小鼠中消失，而在对照- mr小鼠中没有。综上所述，脂肪细胞- mr上调导致收缩性受损，内皮功能得以保留，血压正常。弹性增加可能导致收缩不足。我们还确定了脂肪细胞MR和动脉之间的功能性串扰，并描述了涉及氧化还原敏感的PKG-1和Rho激酶的新机制。我们的研究结果表明，来自Adipo-MROE的脂肪组织分泌的血管活性因子优先影响血管平滑肌细胞而不是内皮细胞。我们的发现可能对肥胖/肥胖具有重要意义，因为脂肪细胞- mr表达/信号放大，血管风险增加。
Mineralocorticoid receptor (MR) expression is increased in adipose tissue from obese individuals and animals. We previously demonstrated that adipocyte-MR overexpression (Adipo-MROE) in mice is associated with metabolic changes. Whether adipocyte MR directly influences vascular function in these mice is unknown. We tested this hypothesis in resistant mesenteric arteries from Adipo-MROE mice using myography and in cultured adipocytes. Molecular mechanisms were probed in vessels/vascular smooth muscle cells and adipose tissue/adipocytes and focused on redox-sensitive pathways, Rho kinase activity, and protein kinase G type-1 (PKG-1) signaling. Adipo-MROE versus control-MR mice exhibited reduced vascular contractility, associated with increased generation of adipocyte-derived hydrogen peroxide, activation of vascular redox-sensitive PKG-1, and downregulation of Rho kinase activity. Associated with these vascular changes was increased elastin content in Adipo-MROE. Inhibition of PKG-1 with Rp-8-Br-PET-cGMPS normalized vascular contractility in Adipo-MROE. In the presence of adipocyte-conditioned culture medium, anticontractile effects of the adipose tissue were lost in Adipo-MROE mice but not in control-MR mice. In conclusion, adipocyte-MR upregulation leads to impaired contractility with preserved endothelial function and normal blood pressure. Increased elasticity may contribute to hypocontractility. We also identify functional cross talk between adipocyte MR and arteries and describe novel mechanisms involving redox-sensitive PKG-1 and Rho kinase. Our results suggest that adipose tissue from Adipo-MROE secrete vasoactive factors that preferentially influence vascular smooth muscle cells rather than endothelial cells. Our findings may be important in obesity/adiposity where adipocyte-MR expression/signaling is amplified and vascular risk increased.