Background: Cardiovascular complications are the leading cause of death and elevated levels of asymmetric dimethyarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are implicated in their pathophysiology. We investigated the role of DDAH1 (dimethylarginine dimethylaminohydrolase 1), an enzyme hydrolyzing ADMA, in prevention of cardiovascular remodeling during hypertension. We hypothesized that the animals overexpressing DDAH1 will be protected from Ang II-induced end organ damage. Methods and Results: Angiotensin II (ANGII) was infused in two doses: 0.75 and 1.5 mg/kg/day in DDAH1 transgenic mice (TG) and wild type (WT) littermates for two or four weeks. Echocardiography was performed in the first and fourth week of the infusion, systolic blood pressure (SBP) was measured weekly and cardiac hypertrophy and vascular remodeling was assessed by histology. Increase in SBP after one week of ANGII infusion was not different between the groups, while TG mice had lower SBP at later time points. TG mice were protected from cardiovascular remodeling after 2 weeks of ANGII infusion in the high dose and after 4 weeks in the moderate dose. TG mice had higher left ventricular lumen-to-wall ratio, lower cardiomyocyte cross sectional area and less interstitial fibrosis as compared to WT controls. In aorta, TG mice had less adventitial fibrosis, lower medial thickness with preserved elastin content, lower counts of inflammatory cells, lower levels of active matrix metalloproteinase-2 and showed better endothelium-dependent relaxation. Conclusions: We demonstrated that overexpression of DDAH1 protects from ANGII-induced cardiovascular remodeling and progression of hypertension by preserving endothelial function and limiting inflammation.

中文翻译：

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二甲基精氨酸二甲氨基水解酶 1 的过度表达可防止血管紧张素 II 诱导的心脏肥大和血管重塑

背景：心血管并发症是导致死亡的主要原因，并且不对称二甲基精氨酸 (ADMA)（一种内源性一氧化氮合酶抑制剂）水平升高与其病理生理学有关。我们研究了 DDAH1（二甲基精氨酸二甲氨基水解酶 1），一种水解 ADMA 的酶，在预防高血压期间心血管重塑中的作用。我们假设过表达 DDAH1 的动物将免受 Ang II 诱导的终末器官损伤。方法和结果：血管紧张素 II (ANGII) 在 DDAH1 转基因小鼠 (TG) 和野生型 (WT) 同窝仔鼠中以两种剂量输注：0.75 和 1.5 mg/kg/天，持续两周或四个星期。在输注的第一周和第四周进行了超声心动图检查，每周测量收缩压 (SBP)，并通过组织学评估心脏肥大和血管重塑。ANGII 输注一周后 SBP 的增加在各组之间没有差异，而 TG 小鼠在较晚的时间点具有较低的 SBP。在高剂量的 ANGII 输注 2 周后和中等剂量的 4 周后，TG 小鼠免受心血管重塑。与 WT 对照相比，TG 小鼠具有更高的左心室腔壁比、更低的心肌细胞横截面积和更少的间质纤维化。在主动脉中，TG 小鼠的外膜纤维化较少，中层厚度较低且弹性蛋白含量保持不变，炎症细胞数量较少，活性基质金属蛋白酶 2 水平较低，并表现出更好的内皮依赖性松弛。结论：