Hollestelle Saskia C G, De Vries Margreet R, Van Keulen J Karlijn, Schoneveld Arjan H, Vink Aryan, Strijder Chaylendra F, Van Middelaar Ben J, Pasterkamp Gerard, Quax Paul H A, De Kleijn Dominique P V
Experimental Cardiology Laboratory, University Medical Center, Room G02-523, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Circulation. 2004 Jan 27;109(3):393-8. doi: 10.1161/01.CIR.0000109140.51366.72. Epub 2003 Dec 29.
Toll-like receptor 4 (Tlr4) is the receptor for exogenous lipopolysaccharides (LPS). Expression of endogenous Tlr4 ligands, heat shock protein 60 (Hsp60) and extra domain A of fibronectin, has been observed in arthritic and oncological specimens in which matrix turnover is an important feature. In atherosclerosis, outward remodeling is characterized by matrix turnover and a structural change in arterial circumference and is associated with a vulnerable plaque phenotype. Since Tlr4 ligands are expressed during matrix turnover, we hypothesized that Tlr4 is involved in arterial remodeling.
In a femoral artery cuff model in the atherosclerotic ApoE3 (Leiden) transgenic mouse, Tlr4 activation by LPS stimulated plaque formation and subsequent outward arterial remodeling. With the use of the same model in wild-type mice, neointima formation and outward remodeling occurred. In Tlr4-deficient mice, however, no outward arterial remodeling was observed independent of neointima formation. Carotid artery ligation in wild-type mice resulted in outward remodeling without neointima formation in the contralateral artery. This was associated with an increase in Tlr4 expression and EDA and Hsp60 mRNA levels. In contrast, outward remodeling was not observed after carotid ligation in Tlr4-deficient mice.
These findings provide genetic evidence that Tlr4 is involved in outward arterial remodeling, probably through upregulation of Tlr4 and Tlr4 ligands.
Toll样受体4（Tlr4）是外源性脂多糖（LPS）的受体。在内源性Tlr4配体，即热休克蛋白60（Hsp60）和纤连蛋白额外结构域A的表达，已在关节炎和肿瘤标本中观察到，其中基质更新是一个重要特征。在动脉粥样硬化中，向外重塑的特征是基质更新以及动脉周长的结构变化，并与易损斑块表型相关。由于Tlr4配体在基质更新过程中表达，我们推测Tlr4参与动脉重塑。
在动脉粥样硬化的ApoE3（莱顿）转基因小鼠的股动脉袖带模型中，LPS激活Tlr4刺激斑块形成及随后的动脉向外重塑。在野生型小鼠中使用相同模型，出现了新生内膜形成和向外重塑。然而，在Tlr4缺陷小鼠中，无论新生内膜形成与否，均未观察到动脉向外重塑。野生型小鼠的颈动脉结扎导致对侧动脉出现向外重塑但无新生内膜形成。这与Tlr4表达以及EDA和Hsp60 mRNA水平增加有关。相比之下，Tlr4缺陷小鼠颈动脉结扎后未观察到向外重塑。
这些发现提供了遗传学证据，表明Tlr4可能通过上调Tlr4及其配体参与动脉向外重塑。
