Kopaliani Irakli, Jarzebska Natalia, Billoff Silke, Kolouschek Anne, Martens-Lobenhoffer Jens, Bornstein Stefan R, Bode-Böger Stefanie M, Ragavan Vinitha N, Weiss Norbert, Mangoni Arduino A, Deussen Andreas, Rodionov Roman N
Department of Physiology, Medical Faculty, Dresden University of Technology, Dresden, Germany.
University Center for Vascular Medicine, Dresden University of Technology, Dresden, Germany.
Am J Physiol Heart Circ Physiol. 2021 Nov 1;321(5):H825-H838. doi: 10.1152/ajpheart.00064.2021. Epub 2021 Sep 17.
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 dimethylarginine dimethylaminohydrolase 1 (DDAH1), an enzyme hydrolyzing ADMA, in prevention of cardiovascular remodeling during hypertension. We hypothesized that the animals overexpressing DDAH1 will be protected from angiotensin II (ANG II)-induced end organ damage. Angiotensin II (ANG II) was infused in two doses: 0.75 and 1.5 mg/kg/day in DDAH1 transgenic mice (DDAH1 TG) and wild-type (WT) littermates for 2 or 4 wk. Echocardiography was performed in the first and fourth weeks of the infusion, systolic blood pressure (SBP) was measured weekly, and cardiac hypertrophy and vascular remodeling was assessed by histology. Increase in SBP after 1 wk of ANG II infusion was not different between the groups, whereas TG mice had lower SBP at later time points. TG mice were protected from cardiovascular remodeling after 2 wk of ANG II infusion in the high dose and after 4 wk in the moderate dose. TG mice had higher left ventricular lumen-to-wall ratio, lower cardiomyocyte cross-sectional area, and less interstitial fibrosis compared with 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. We demonstrated that overexpression of DDAH1 protects from ANG II-induced cardiovascular remodeling and progression of hypertension by preserving endothelial function and limiting inflammation. We showed that overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects from angiotensin II-induced cardiovascular damage, progression of hypertension, and adverse vascular remodeling in vivo. This protective effect is associated with decreased levels of asymmetric dimethylarginine, preservation of endothelial function, inhibition of cardiovascular inflammation, and lower activity of matrix metalloproteinase-2. Our findings are highly clinically relevant, because they suggest that upregulation of DDAH1 might be a promising therapeutic approach against angiotensin II-induced end organ damage.
心血管并发症是主要的死亡原因，而不对称二甲基精氨酸（ADMA）水平升高，一种一氧化氮合酶的内源性抑制剂，与其病理生理学有关。我们研究了二甲基精氨酸二甲胺水解酶1（DDAH1），一种水解ADMA的酶，在高血压期间预防心血管重塑中的作用。我们假设过表达DDAH1的动物将免受血管紧张素II（ANG II）诱导的终末器官损伤。血管紧张素II（ANG II）以两种剂量输注：在DDAH1转基因小鼠（DDAH1 TG）和野生型（WT）同窝小鼠中分别为0.75和1.5 mg/kg/天，持续2或4周。在输注的第一周和第四周进行超声心动图检查，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。ANG II输注第1周后SBP的升高在各组之间无差异，而TG小鼠在后期时间点的SBP较低。高剂量ANG II输注2周后和中等剂量输注4周后，TG小鼠免受心血管重塑。与WT对照组相比，TG小鼠的左心室腔壁比更高，心肌细胞横截面积更小，间质纤维化更少。在主动脉中，TG小鼠的外膜纤维化更少，中膜厚度更低但弹性蛋白含量保持不变，炎症细胞计数更低，活性基质金属蛋白酶-2水平更低，并表现出更好的内皮依赖性舒张。我们证明，DDAH1的过表达通过保留内皮功能和限制炎症，保护免受ANG II诱导的心血管重塑和高血压进展。我们表明，二甲基精氨酸二甲胺水解酶1（DDAH1）的过表达在体内保护免受血管紧张素II诱导的心血管损伤、高血压进展和不良血管重塑。这种保护作用与不对称二甲基精氨酸水平降低、内皮功能保留、心血管炎症抑制以及基质金属蛋白酶-2活性降低有关。我们的发现具有高度临床相关性，因为它们表明DDAH1的上调可能是对抗血管紧张素II诱导的终末器官损伤的一种有前景的治疗方法。
