Division of Cardiothoracic Surgery, Tufts Medical Center, Boston, Mass 02111, USA.
J Thorac Cardiovasc Surg. 2013 Jun;145(6):1642-9, 1649.e1. doi: 10.1016/j.jtcvs.2012.08.007. Epub 2012 Sep 13.
Vein graft failure rates resulting from adverse graft remodeling remain high with no effective therapy. The mineralocorticoid receptor (MR) plays a role in pathologic arterial remodeling. We demonstrated recently that the 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 the 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 the MR, 11-β-hydroxysteroid dehydrogenase 2, angiotensin type 1 receptor, and the angiotensin-converting enzyme are expressed in whole HSVSMC. MR and 11-β-hydroxysteroid dehydrogenase 2 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 per day), reduces maximal vein graft intima-media thickness by 68%, with an associated reduction in graft inflammatory cell infiltration and fibrosis.
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.
由于不利的移植物重塑导致的静脉移植物失败率仍然很高，而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。我们最近证明，MR 在移植后静脉组织中上调，并假设 MR 抑制将减少静脉移植物重塑。
使用逆转录聚合酶链反应和免疫印迹检测人静脉和原代人隐静脉平滑肌细胞（HSVSMC）中 MR 和肾素-血管紧张素-醛固酮系统的其他成分的表达。腺病毒报告基因测定用于探索 HSVSMC 中的 MR 转录活性。在小鼠静脉移植物模型中，研究了 MR 抑制对静脉移植物重塑的体内作用。
编码 MR、11-β-羟类固醇脱氢酶 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 HSVSMC 中表达。证实了 MR 和 11-β-羟类固醇脱氢酶 2 蛋白的表达，并在 HSVSMC 中证实了生理醛固酮浓度下的 MR 依赖性转录调节。用 MR 拮抗剂螺内酯（不降低血压的剂量，每天 20mg/kg）治疗小鼠，可使最大静脉移植物内膜-中膜厚度减少 68%，同时减少移植物炎症细胞浸润和纤维化。
MR 在人静脉组织和细胞中表达，并调节 HSVSMC 中的基因表达，以响应生理醛固酮浓度。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 拮抗剂作为新的治疗方法来维持静脉移植物通畅的潜力。
