精氨酸酶1介导抗炎和平滑肌细胞增殖促动脉粥样硬化斑块稳定分子机制研究

The macrophage is the inflammatory cell in atherosclerotic plaque. Increased macrophage infiltration and/or activation may promote atherosclerotic plaque growth and progression by secreting inflammatory cytokines. As well, it may induce collagen breakdown in the fibrous cap by secreting matrix metalloproteinases and other proteases, thus contributing to vulnerability to plaque rupture. However, not all macrophages exhibit the inflammatory phenotype. Macrophages in atherosclerotic plaque are classified into 2 types: classical (proinflammatory, M1) and reparative (anti-inflammatory, M2). The increased infiltration of classical type or decreased activation of the reparative phenotype may contribute to chronic inflammation. Inflammatory processes are involved in all phases of the atherosclerotic pathological process. A major effective molecule from inflammatory macrophages is nitric oxide (NO), which is synthesized by inducible NO synthase (iNOS) from L-arginine catalysis. NO synthesized by iNOS in inflammatory macrophages was initially considered a major component of atherosclerosis development and a main contributor to inflammation, but reparative macrophages have anti-inflammation effects during inflammatory disease. For example, the delivery of reparative macrophages reduced colonic inflammation in mice. Arginase I (Arg I) has been considered a marker of reparative macrophages. Although Arg I is involved in immune deactivation and the inflammatory response, its role in macrophage activation remains unknown. Unlike its generous constitutive expression in mammalian liver, Arg I expression is slight in extrahepatic tissue and tightly regulated by exogenous stimulus such as interleukin 4 (IL-4) and IL-13. Arg I has a role in metabolization of nitrogen into polyamines, which is important for cell proliferation and wound healing, as well as substrate competition with other L-arginine-dependent enzymes, such as NOS. iNOS is an important proinflammatory cytokine which is often induced by macrophage exposure to pro-inflammatory cytokines. Furthermore, iNOS is consistently induced in atherosclerotic vessels of humans and experimental animals, promoting inflammation and decreasing collagen content in lesions. Although Arg I may be a candidate gene of atherosclerosis resistance, its role in atherosclerosis is still controversial. We aimed to investigate the role and mechanism of Arg I on plaque stabilization in unruptured, atherosclerotic lesions of rabbits.

研究表明：修复性巨噬细胞能促进动脉粥样斑块稳定。Arg1 被认为是修复型巨噬细胞的标志物。尽管Arg1促进免疫失活和参与炎症反应，它在巨噬细胞活化中的作用仍然未知。Arg 1 在肝外组织表达极少，可被外源性刺激物如白介素4（IL-4）和白介素13（IL-13）密切调节。Arg1 可代谢氮为多胺类，参与细胞增殖和创伤愈合，并且与其他L-精氨酸依赖的酶，如NOS竞争催化底物。iNOS是一种重要的促炎分子，通常由巨噬细胞在促炎细胞因子作用下产生。在人类和实验性动物的动脉粥样硬化血管中持续产生iNOS，发挥促炎和减少病损处胶原含量的作用。尽管Arg1可能是抗动脉粥样硬化的侯选基因，但是它在动脉粥样硬化发生中的作用仍有争议, Arg1 在动脉粥样硬化病变中对斑块稳定性的作用及其机制也不明确。本申请拟通过研究兔未破裂的动脉粥样硬化斑块，探讨Arg 1对斑块稳定性的作用及分子机制。