Peyton Kelly J, Ensenat Diana, Azam Mohammed A, Keswani Amit N, Kannan Sankaranarayanan, Liu Xiao-ming, Wang Hong, Tulis David A, Durante William
Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA.
Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):488-94. doi: 10.1161/ATVBAHA.108.183392. Epub 2009 Jan 22.
Arginase stimulates the proliferation of cultured vascular smooth muscle cells (VSMCs); however, the influence of arginase on VSMC growth in vivo is not known. This study investigated the impact of arginase on cell cycle progression and neointima formation after experimental arterial injury.
Balloon injury of rat carotid arteries resulted in a sustained increase in arginase activity in the vessel wall and the induction of arginase I protein in both the media and neointima of injured vessels. Furthermore, local perivascular application of the potent and selective arginase inhibitors S-(2-boronoethyl)-L-cysteine (BEC) or N(G)-hydroxy-nor-L-arginine (L-OHNA) immediately after injury markedly attenuated medial and neointimal DNA synthesis and neointima formation. Substantial arginase I protein and arginase activity was also detected in rat cultured aortic VSMCs. Moreover, treatment of VSMCs with BEC or L-OHNA, or knockdown of arginase I protein, arrested cells in the G(0)/G(1) phase of the cell cycle and induced the expression of the cyclin-dependent protein kinase inhibitor, p21.
This study demonstrates that arginase is essential for VSMCs to enter the cell cycle and that arginase I contributes to the remodeling response after arterial injury. Arginase I represents a potentially new therapeutic target for the treatment of vasculoproliferative disorders.
精氨酸酶可刺激培养的血管平滑肌细胞（VSMC）增殖；然而，精氨酸酶在体内对VSMC生长的影响尚不清楚。本研究调查了精氨酸酶对实验性动脉损伤后细胞周期进程和新生内膜形成的影响。
大鼠颈动脉球囊损伤导致血管壁中精氨酸酶活性持续增加，并在损伤血管的中膜和新生内膜中诱导精氨酸酶I蛋白表达。此外，损伤后立即在局部血管周围应用强效选择性精氨酸酶抑制剂S-(2-硼乙基)-L-半胱氨酸（BEC）或N(G)-羟基-L-精氨酸（L-OHNA），可显著减弱中膜和新生内膜的DNA合成以及新生内膜形成。在大鼠培养的主动脉VSMC中也检测到大量的精氨酸酶I蛋白和精氨酸酶活性。此外，用BEC或L-OHNA处理VSMC，或敲低精氨酸酶I蛋白，可使细胞停滞在细胞周期的G(0)/G(1)期，并诱导细胞周期蛋白依赖性蛋白激酶抑制剂p21的表达。
本研究表明精氨酸酶是VSMC进入细胞周期所必需的，且精氨酸酶I参与动脉损伤后的重塑反应。精氨酸酶I代表了一种治疗血管增殖性疾病的潜在新治疗靶点。
