Kapelouzou Alkistis, Giaglis Stavros, Peroulis Michalis, Katsimpoulas Michalis, Moustardas Petros, Aravanis Chrysostomos V, Kostakis Alkiviadis, Karayannakos Panagiotis E, Cokkinos Dennis V
Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
J Vasc Res. 2017;54(3):156-169. doi: 10.1159/000457797. Epub 2017 May 5.
Atherosclerosis is the major cause of cardiovascular disease; hypercholesterolemia is a major risk factor. We hypothesized that specific TLR members (TLR2, TLR3, TLR4, TLR8) may play a role in atherosclerosis progression and its accompanying inflammatory response. We determined the association of atherosclerotic lesions and TLR mRNA expression in different aortic sites. We also assessed the effects of fluvastatin (Flu) treatment on TLR expression and plaque characteristics.
Male rabbits, fed with an atherogenic diet for a duration of 3 months, were screened for advanced atherosclerotic lesions in the aorta. Additional animals received normal diet or normal diet plus Flu for 1 additional month. TLR mRNA expression in various thoracic and abdominal aortic segments was assessed, together with atherosclerotic changes.
After high lipid diet, the atherosclerotic burden increased more in the abdominal than in the thoracic aorta; TLR2, 3, 4, and 8 also increased significantly. Flu decreased atherosclerotic plaque, calcium deposition, lipid cores, intraplaque hemorrhage, erythrocyte membranes, endothelial cells, and macrophage infiltration, while increasing smooth muscle cells in plaques of both aortic segments; it also lowered TLR2, 3, 4, and 8 expression in all aortic segments to a stronger degree than resumption of normal diet. There was a strong association between blood and tissue parameters during experimental period and finally a strong correlation found between these parameters with mRNA of TLR2, 3, 4, and 8 in various stages.
For the first time TLR2, 3, 4, and 8 mRNA expression is prospectively explored after hypercholesterolemic diet in the rabbit model. TLR2, 3, 4, and 8 mRNA expression is strongly upregulated and correlates with the progression of atherosclerosis in the aorta. Flu significantly inhibited this progress and reduced inflammation via TLR downregulation which was strongly associated with regression of plaque morphology and atherosclerosis promoting factors.
动脉粥样硬化是心血管疾病的主要病因；高胆固醇血症是主要危险因素。我们推测特定的Toll样受体（TLR）成员（TLR2、TLR3、TLR4、TLR8）可能在动脉粥样硬化进展及其伴随的炎症反应中起作用。我们确定了不同主动脉部位动脉粥样硬化病变与TLR mRNA表达的关联。我们还评估了氟伐他汀（Flu）治疗对TLR表达和斑块特征的影响。
雄性兔子喂食致动脉粥样硬化饮食3个月，筛选主动脉中晚期动脉粥样硬化病变。另外的动物再接受1个月的正常饮食或正常饮食加Flu。评估胸主动脉和腹主动脉各段的TLR mRNA表达以及动脉粥样硬化变化。
高脂饮食后，腹主动脉的动脉粥样硬化负担比胸主动脉增加更多；TLR2、3、4和8也显著增加。Flu减少了两个主动脉段斑块中的动脉粥样硬化斑块、钙沉积、脂质核心、斑块内出血、红细胞膜、内皮细胞和巨噬细胞浸润，同时增加了平滑肌细胞；它还比恢复正常饮食更显著地降低了所有主动脉段中TLR2、3、4和8的表达。实验期间血液和组织参数之间有很强的关联，最终在各个阶段这些参数与TLR2、3、4和8的mRNA之间发现了很强的相关性。
首次在兔模型中高胆固醇饮食后前瞻性地探究了TLR2、3、4和8 mRNA的表达。TLR2、3、4和8 mRNA表达强烈上调并与主动脉中动脉粥样硬化的进展相关。Flu通过下调TLR显著抑制了这一进展并减轻了炎症，这与斑块形态和动脉粥样硬化促进因子的消退密切相关。
