Mechanisms underlying the cardiac antifibrotic effects of losartan metabolites
Mechanisms underlying the cardiac antifibrotic effects of losartan metabolites
复制标题
DOI：
10.1038/srep41865
复制
发表时间：
2017-02-03
影响因子：
4.6
通讯作者：
Ravassa, Susana
中科院分区：
文献类型：
--
作者：
Luis Miguel-Carrasco, Jose;Beaumont, Javier;Ravassa, Susana
过度的心肌胶原沉积和交联 (CCL) 是由赖氨酰氧化酶 (LOX) 调节的过程，决定左心室 (LV) 僵硬和功能障碍。血管紧张素 II 拮抗剂氯沙坦代谢为 EXP3179 和 EXP3174 代谢物，可减少高血压患者的心肌纤维化和左心室僵硬度。我们的目的是在高血压伴心肌纤维化的实验模型中研究氯沙坦代谢物对心肌 LOX 和 CCL 的差异影响，以及 EXP3179 和 EXP3174 是否改变成纤维细胞中 LOX 的表达和活性。在用 NG-硝基-L-精氨酸甲酯 (L-NAME) 治疗的大鼠中，给予 EXP3179 完全阻止了 LOX、CCL 和结缔组织生长因子 (CTGF) 的增加以及纤维化，但血压 (BP) 没有正常化。相比之下，给予 EXP3174 可使血压正常化并减轻纤维化，但不会改变 LOX、CCL 和 CTGF。在 TGF-β(1) 刺激的成纤维细胞中，EXP3179 抑制 CTGF 和 LOX 的表达和活性，IC50 值低于 EXP3174。我们的结果表明，尽管 EXP3179 的抗高血压作用较低，但其抗纤维化功效高于 EXP3174，这可能是通过其防止 LOX 和 CCL 过量的能力实现的。这表明 EXP3179 的抗纤维化作用可能部分是通过阻断成纤维细胞中 CTGF 诱导的 LOX 介导的。
Excessive myocardial collagen deposition and cross-linking (CCL), a process regulated by lysyl oxidase (LOX), determines left ventricular (LV) stiffness and dysfunction. The angiotensin II antagonist losartan, metabolized to the EXP3179 and EXP3174 metabolites, reduces myocardial fibrosis and LV stiffness in hypertensive patients. Our aim was to investigate the differential influence of losartan metabolites on myocardial LOX and CCL in an experimental model of hypertension with myocardial fibrosis, and whether EXP3179 and EXP3174 modify LOX expression and activity in fibroblasts. In rats treated with NG-nitro-L-arginine methyl ester (L-NAME), administration of EXP3179 fully prevented LOX, CCL and connective tissue growth factor (CTGF) increase, as well as fibrosis, without normalization of blood pressure (BP). In contrast, administration of EXP3174 normalized BP and attenuated fibrosis but did not modify LOX, CCL and CTGF. In TGF-beta(1)-stimulated fibroblasts, EXP3179 inhibited CTGF and LOX expression and activity with lower IC50 values than EXP3174. Our results indicate that, despite a lower antihypertensive effect, EXP3179 shows higher anti-fibrotic efficacy than EXP3174, likely through its ability to prevent the excess of LOX and CCL. It is suggested that the anti-fibrotic effect of EXP3179 may be partially mediated by the blockade of CTGF-induced LOX in fibroblasts.