Mineralocorticoid receptor antagonism inhibits vein graft remodeling in mice.
Mineralocorticoid receptor antagonism inhibits vein graft remodeling in mice.
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DOI：
10.1016/j.jtcvs.2012.08.007
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发表时间：
2013-06
影响因子：
6
通讯作者：
Jaffe, Iris Z.
中科院分区：
文献类型：
--
作者：
Ehsan, Afshin;McGraw, Adam P.;Aronovitz, Mark J.;Galayda, Carol;Conte, Michael S.;Karas, Richard H.;Jaffe, Iris Z.
由于移植物不良重塑导致的静脉移植物失败率仍然很高，没有有效的治疗方法。盐皮质激素受体（MR）在病理性动脉重塑中起作用。我们最近证实了移植后静脉组织中MR上调，并假设MR抑制会减少静脉移植物重塑。应用逆转录聚合酶链反应（RT-PCR）和免疫印迹技术检测人静脉和原代人大隐静脉平滑肌细胞（HSVSMC）中MR和肾素-血管紧张素-醛固酮系统其它组分的表达。用腺病毒报告基因检测HSVSMC中MR的转录活性。在小鼠静脉移植物模型中表征MR抑制对体内静脉移植物重塑的影响。编码MR、11-β-羟基类固醇脱氢酶2（11bHSD 2）、血管紧张素1型受体和血管紧张素转换酶的信使RNA在整个人静脉和HSVSMC中表达。证实了HSVSMC中MR和11β HSD 2蛋白的表达，并且在生理性醛固酮浓度下证实了MR依赖性转录调节。在不降低血压的剂量（20 mg/kg/天）下，用MR拮抗剂螺内酯治疗小鼠，使最大静脉移植物内膜-中层厚度降低68%，移植物炎性细胞浸润和纤维化相关减少。MR在人静脉组织和细胞中表达，并响应生理性醛固酮浓度调节HSVSMC中的基因表达。在体内，MR抑制减少静脉移植物增厚和炎症。这些临床前数据支持使用MR拮抗剂作为保持静脉移植物通畅性的新型治疗方法的潜力。
Vein graft failure rates due to adverse graft remodeling remain high with no effective therapy. The mineralocorticoid receptor (MR) plays a role in pathologic arterial remodeling. We have recently demonstrated that MR is upregulated in venous tissues after grafting and hypothesized that MR inhibition would reduce vein graft remodeling. Reverse transcription polymerase chain reaction and immunoblotting were used to examine the expression of MR and other components of the renin-angiotensin-aldosterone system in human vein and primary human saphenous vein smooth muscle cells (HSVSMC). Adenoviral reporter gene assays were used to explore MR transcriptional activity in HSVSMC. The effect of MR inhibition on vein graft remodeling in vivo was characterized in a mouse vein graft model. Messenger RNAs encoding MR, 11-β-hydroxysteroid dehydrogenase 2 (11bHSD2), angiotensin type-1 receptor, and the angiotensin converting enzyme are expressed in whole human vein and in HSVSMC. MR and 11βHSD2 protein expression is confirmed and MR-dependent transcriptional regulation is demonstrated at physiologic aldosterone concentrations in HSVSMC. Treatment of mice with the MR antagonist spironolactone, at doses that do not lower blood pressure (20 mg/kg/day), reduces maximal vein graft intima-media thickness by 68%, with an associated reduction in graft inflammatory cell infiltration and fibrosis. The MR is expressed in human venous tissue and cells and modulates gene expression in HSVSMC in response to physiologic aldosterone concentrations. In vivo, MR inhibition reduces vein graft thickening and inflammation. These preclinical data support the potential to use MR antagonists as novel treatments to preserve vein graft patency.
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DOI：
10.1161/atvbaha.111.229070
发表时间：
2011-08
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Newfell BG;Iyer LK;Mohammad NN;McGraw AP;Ehsan A;Rosano G;Huang PL;Mendelsohn ME;Jaffe IZ
通讯作者：
Jaffe IZ
影响因子：
15.9
作者：
Jaffe, Iris Z.;Newfell, Brenna G.;Mendelsohn, Michael E.
通讯作者：
Mendelsohn, Michael E.
影响因子：
4.3
作者：
Owens, Christopher D.;Rybicki, Frank J.;Conte, Michael S.
通讯作者：
Conte, Michael S.
影响因子：
8.3
作者：
Ohtani, Kisho;Egashira, Kensuke;Sunagawa, Kenji
通讯作者：
Sunagawa, Kenji
影响因子：
7.3
作者：
Cassis, LA;Helton, MJ;Daugherty, A
通讯作者：
Daugherty, A