Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling.
Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling.
复制标题
DOI：
10.1038/s41598-018-21087-5
复制
发表时间：
2018-02-13
影响因子：
4.6
通讯作者：
Touyz RM
中科院分区：
文献类型：
--
作者：
Nguyen Dinh Cat A;Callera GE;Friederich-Persson M;Sanchez A;Dulak-Lis MG;Tsiropoulou S;Montezano AC;He Y;Briones AM;Jaisser F;Touyz RM
醛固酮/盐皮质激素受体（MR）的激活与糖尿病血管功能障碍有关。潜在的机制是难以捉摸的。因此，我们研究了Rho激酶（ROCK）在糖尿病模型中醛固酮/MR信号传导和血管功能障碍中的作用。用MR拮抗剂（MRA，坎利酸钾，30 mg/kg/天，4周）或ROCK抑制剂法舒地尔（30 mg/kg/天，3周）处理糖尿病肥胖小鼠（db/db）和对照小鼠（db/+）。db/db与db/+相比，血浆醛固酮升高。这与血管MR信号增强有关。去甲肾上腺素（NE）诱导的收缩在db/db小鼠的动脉中增加。这些反应在用坎利酸盐或法舒地尔处理的小鼠中减弱。Db/db小鼠表现出肥大性重塑和动脉僵硬度增加，通过MR阻断得到改善。db/+和db/db去极化动脉之间的血管钙敏感性相似。db/db小鼠的血管过度收缩与肌球蛋白轻链磷酸化增加和PKG-1α表达减少相关。血管RhoA/ROCK信号传导和促炎性和促纤维化标志物的表达在db/db小鼠中被夸大，这种作用被MRA减弱。法舒地尔，而不是MRA，改善血管胰岛素敏感性在db/db小鼠，证明了正常化的Irs 1磷酸化。我们的数据确定了涉及MR-RhoA/ROCK-PKG-1的新途径，这些途径是糖尿病小鼠血管功能障碍和损伤的基础。
Activation of aldosterone/mineralocorticoid receptors (MR) has been implicated in vascular dysfunction of diabetes. Underlying mechanisms are elusive. Therefore, we investigated the role of Rho kinase (ROCK) in aldosterone/MR signaling and vascular dysfunction in a model of diabetes. Diabetic obese mice (db/db) and control counterparts (db/+) were treated with MR antagonist (MRA, potassium canrenoate, 30 mg/kg/day, 4 weeks) or ROCK inhibitor, fasudil (30 mg/kg/day, 3 weeks). Plasma aldosterone was increased in db/db versus db/+. This was associated with enhanced vascular MR signaling. Norepinephrine (NE)-induced contraction was increased in arteries from db/db mice. These responses were attenuated in mice treated with canrenoate or fasudil. Db/db mice displayed hypertrophic remodeling and increased arterial stiffness, improved by MR blockade. Vascular calcium sensitivity was similar between depolarized arteries from db/+ and db/db. Vascular hypercontractility in db/db mice was associated with increased myosin light chain phosphorylation and reduced expression of PKG-1α. Vascular RhoA/ROCK signaling and expression of pro-inflammatory and pro-fibrotic markers were exaggerated in db/db mice, effects that were attenuated by MRA. Fasudil, but not MRA, improved vascular insulin sensitivity in db/db mice, evidenced by normalization of Irs1 phosphorylation. Our data identify novel pathways involving MR-RhoA/ROCK-PKG-1 that underlie vascular dysfunction and injury in diabetic mice.
登录
查看更多内容
DOI：
10.1161/hypertensionaha.113.01967
发表时间：
2014-03
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Galmiche G;Pizard A;Gueret A;El Moghrabi S;Ouvrard-Pascaud A;Berger S;Challande P;Jaffe IZ;Labat C;Lacolley P;Jaisser F
通讯作者：
Jaisser F
影响因子：
7.3
作者：
Guilluy, C;Sauzeau, V;Loirand, G
通讯作者：
Loirand, G
影响因子：
3.7
作者：
Noda K;Nakajima S;Godo S;Saito H;Ikeda S;Shimizu T;Enkhjargal B;Fukumoto Y;Tsukita S;Yamada T;Katagiri H;Shimokawa H
通讯作者：
Shimokawa H
影响因子：
7.7
作者：
Cat, Aurelie Nguyen Dinh;Antunes, Tayze T.;Touyz, Rhian M.
通讯作者：
Touyz, Rhian M.
影响因子：
4.8
作者：
Bruder-Nascimento T;da Silva MA;Tostes RC
通讯作者：
Tostes RC