Lucas Alexandra R, Verma Raj K, Dai Erbin, Liu Liying, Chen Hao, Kesavalu Sheela, Rivera Mercedes, Velsko Irina, Ambadapadi Sriram, Chukkapalli Sasanka, Kesavalu Lakshmyya
Division of Cardiovascular Medicine, Departments of Medicine and Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
Department of Periodontology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America.
PLoS One. 2014 Oct 29;9(10):e111353. doi: 10.1371/journal.pone.0111353. eCollection 2014.
Thrombotic occlusion of inflammatory plaque in coronary arteries causes myocardial infarction. Treatment with emergent balloon angioplasty (BA) and stent implant improves survival, but restenosis (regrowth) can occur. Periodontal bacteremia is closely associated with inflammation and native arterial atherosclerosis, with potential to increase restenosis. Two virus-derived anti-inflammatory proteins, M-T7 and Serp-1, reduce inflammation and plaque growth after BA and transplant in animal models through separate pathways. M-T7 is a broad spectrum C, CC and CXC chemokine-binding protein. Serp-1 is a serine protease inhibitor (serpin) inhibiting thrombotic and thrombolytic pathways. Serp-1 also reduces arterial inflammation and improves survival in a mouse herpes virus (MHV68) model of lethal vasculitis. In addition, Serp-1 demonstrated safety and efficacy in patients with unstable coronary disease and stent implant, reducing markers of myocardial damage. We investigate here the effects of Porphyromonas gingivalis, a periodontal pathogen, on restenosis after BA and the effects of blocking chemokine and protease pathways with M-T7 and Serp-1. ApoE-/- mice had aortic BA and oral P. gingivalis infection. Arterial plaque growth was examined at 24 weeks with and without anti-inflammatory protein treatment. Dental plaques from mice infected with P. gingivalis tested positive for infection. Neither Serp-1 nor M-T7 treatment reduced infection, but IgG antibody levels in mice treated with Serp-1 and M-T7 were reduced. P. gingivalis significantly increased monocyte invasion and arterial plaque growth after BA (P<0.025). Monocyte invasion and plaque growth were blocked by M-T7 treatment (P<0.023), whereas Serp-1 produced only a trend toward reductions. Both proteins modified expression of TLR4 and MyD88. In conclusion, aortic plaque growth in ApoE-/- mice increased after angioplasty in mice with chronic oral P. gingivalis infection. Blockade of chemokines, but not serine proteases significantly reduced arterial plaque growth, suggesting a central role for chemokine-mediated inflammation after BA in P. gingivalis infected mice.
冠状动脉中炎性斑块的血栓闭塞会导致心肌梗死。紧急球囊血管成形术（BA）和支架植入治疗可提高生存率，但可能会发生再狭窄（重新生长）。牙周菌血症与炎症和原发性动脉粥样硬化密切相关，有可能增加再狭窄的发生率。两种病毒衍生的抗炎蛋白，M-T7和Serp-1，通过不同途径在动物模型中BA和移植后可减轻炎症和斑块生长。M-T7是一种广谱C、CC和CXC趋化因子结合蛋白。Serp-1是一种丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂），可抑制血栓形成和溶栓途径。Serp-1还可减轻动脉炎症，并提高致死性血管炎小鼠疱疹病毒（MHV68）模型的生存率。此外，Serp-1在不稳定型冠心病和支架植入患者中显示出安全性和有效性，可降低心肌损伤标志物。我们在此研究牙周病原体牙龈卟啉单胞菌对BA后再狭窄的影响，以及用M-T7和Serp-1阻断趋化因子和蛋白酶途径的效果。ApoE-/-小鼠接受主动脉BA和口腔牙龈卟啉单胞菌感染。在有或没有抗炎蛋白治疗的情况下，于24周时检查动脉斑块生长情况。感染牙龈卟啉单胞菌的小鼠的牙菌斑检测呈阳性。Serp-1和M-T7治疗均未降低感染率，但用Serp-1和M-T7治疗的小鼠的IgG抗体水平降低。牙龈卟啉单胞菌在BA后显著增加单核细胞浸润和动脉斑块生长（P<0.025）。M-T7治疗可阻断单核细胞浸润和斑块生长（P<0.023），而Serp-1仅呈现出降低的趋势。两种蛋白均改变了TLR4和MyD88的表达。总之，慢性口腔感染牙龈卟啉单胞菌的小鼠在血管成形术后，ApoE-/-小鼠的主动脉斑块生长增加。趋化因子的阻断而非丝氨酸蛋白酶的阻断可显著降低动脉斑块生长，这表明在牙龈卟啉单胞菌感染的小鼠中，趋化因子介导的炎症在BA后起核心作用。
