Kim Jihee, Zhang Lisheng, Peppel Karsten, Wu Jiao-Hui, Zidar David A, Brian Leigh, DeWire Scott M, Exum Sabrina T, Lefkowitz Robert J, Freedman Neil J
Department of Medicine (Cardiology), Duke University Medical Center, Durham, NC 27710, USA.
Circ Res. 2008 Jul 3;103(1):70-9. doi: 10.1161/CIRCRESAHA.108.172338. Epub 2008 Jun 2.
Atherosclerosis and arterial injury-induced neointimal hyperplasia involve medial smooth muscle cell (SMC) proliferation and migration into the arterial intima. Because many 7-transmembrane and growth factor receptors promote atherosclerosis, we hypothesized that the multifunctional adaptor proteins beta-arrestin1 and -2 might regulate this pathological process. Deficiency of beta-arrestin2 in ldlr(-/-) mice reduced aortic atherosclerosis by 40% and decreased the prevalence of atheroma SMCs by 35%, suggesting that beta-arrestin2 promotes atherosclerosis through effects on SMCs. To test this potential atherogenic mechanism more specifically, we performed carotid endothelial denudation in congenic wild-type, beta-arrestin1(-/-), and beta-arrestin2(-/-) mice. Neointimal hyperplasia was enhanced in beta-arrestin1(-/-) mice, and diminished in beta-arrestin2(-/-) mice. Neointimal cells expressed SMC markers and did not derive from bone marrow progenitors, as demonstrated by bone marrow transplantation with green fluorescent protein-transgenic cells. Moreover, the reduction in neointimal hyperplasia seen in beta-arrestin2(-/-) mice was not altered by transplantation with either wild-type or beta-arrestin2(-/-) bone marrow cells. After carotid injury, medial SMC extracellular signal-regulated kinase activation and proliferation were increased in beta-arrestin1(-/-) and decreased in beta-arrestin2(-/-) mice. Concordantly, thymidine incorporation and extracellular signal-regulated kinase activation and migration evoked by 7-transmembrane receptors were greater than wild type in beta-arrestin1(-/-) SMCs and less in beta-arrestin2(-/-) SMCs. Proliferation was less than wild type in beta-arrestin2(-/-) SMCs but not in beta-arrestin2(-/-) endothelial cells. We conclude that beta-arrestin2 aggravates atherosclerosis through mechanisms involving SMC proliferation and migration and that these SMC activities are regulated reciprocally by beta-arrestin2 and beta-arrestin1. These findings identify inhibition of beta-arrestin2 as a novel therapeutic strategy for combating atherosclerosis and arterial restenosis after angioplasty.
动脉粥样硬化和动脉损伤诱导的内膜增生涉及中膜平滑肌细胞（SMC）增殖并迁移至动脉内膜。由于许多7跨膜受体和生长因子受体可促进动脉粥样硬化，我们推测多功能衔接蛋白β-抑制蛋白1和-2可能调控这一病理过程。Ldlr(-/-)小鼠中β-抑制蛋白2的缺失使主动脉粥样硬化减少40%，并使动脉粥样硬化SMC的发生率降低35%，提示β-抑制蛋白2通过对SMC的作用促进动脉粥样硬化。为更具体地检测这一潜在的致动脉粥样硬化机制，我们对同基因野生型、β-抑制蛋白1(-/-)和β-抑制蛋白2(-/-)小鼠进行颈动脉内皮剥脱术。β-抑制蛋白1(-/-)小鼠的内膜增生增强，而β-抑制蛋白2(-/-)小鼠的内膜增生减弱。内膜细胞表达SMC标志物，并非来源于骨髓祖细胞，这通过绿色荧光蛋白转基因细胞的骨髓移植得以证实。此外，β-抑制蛋白2(-/-)小鼠内膜增生的减少并未因移植野生型或β-抑制蛋白2(-/-)骨髓细胞而改变。颈动脉损伤后，β-抑制蛋白1(-/-)小鼠中膜SMC细胞外信号调节激酶激活和增殖增加，而β-抑制蛋白2(-/-)小鼠中则减少。一致地，β-抑制蛋白1(-/-) SMC中由7跨膜受体诱发的胸苷掺入、细胞外信号调节激酶激活和迁移大于野生型，而β-抑制蛋白2(-/-) SMC中则小于野生型。β-抑制蛋白2(-/-) SMC中的增殖小于野生型，但β-抑制蛋白2(-/-)内皮细胞中的增殖并非如此。我们得出结论，β-抑制蛋白2通过涉及SMC增殖和迁移的机制加重动脉粥样硬化，并且这些SMC活性受到β-抑制蛋白2和β-抑制蛋白1的相互调节。这些发现表明抑制β-抑制蛋白2是对抗动脉粥样硬化和血管成形术后动脉再狭窄的一种新的治疗策略。
