Genetic deletion or TWEAK blocking antibody administration reduce atherosclerosis and enhance plaque stability in mice

Abstract

Clinical complications associated with atherosclerotic plaques arise from luminal obstruction due to plaque growth or destabilization leading to rupture. Tumour necrosis factor ligand superfamily member 12 (TNFSF12) also known as TNF-related weak inducer of apoptosis (TWEAK) is a proinflammatory cytokine that participates in atherosclerotic plaque development, but its role in plaque stability remains unclear. Using two different approaches, genetic deletion of TNFSF12 and treatment with a TWEAK blocking mAb in atherosclerosis-prone mice, we have analysed the effect of TWEAK inhibition on atherosclerotic plaques progression and stability. Mice lacking both TNFSF12 and Apolipoprotein E (TNFSF12−/−ApoE−/−) exhibited a diminished atherosclerotic burden and lesion size in their aorta. Advanced atherosclerotic plaques of TNFSF12−/−ApoE−/− or anti-TWEAK treated mice exhibited an increase collagen/lipid and vascular smooth muscle cell/macrophage ratios compared with TNFSF12+/+ApoE−/− control mice, reflecting a more stable plaque phenotype. These changes are related with two different mechanisms, reduction of the inflammatory response (chemokines expression and secretion and nuclear factor kappa B activation) and decrease of metalloproteinase activity in atherosclerotic plaques of TNFSF12−/−ApoE−/−. A similar phenotype was observed with anti-TWEAK mAb treatment in TNFSF12+/+ApoE−/− mice. Brachiocephalic arteries were also examined since they exhibit additional features akin to human atherosclerotic plaques associated with instability and rupture. Features of greater plaque stability including augmented collagen/lipid ratio, reduced macrophage content, and less presence of lateral xanthomas, buried caps, medial erosion, intraplaque haemorrhage and calcium content were present in TNFSF12−/−ApoE−/− or anti-TWEAK treatment in TNFSF12+/+ApoE−/− mice. Overall, our data indicate that anti-TWEAK treatment has the capacity to diminish proinflamatory response associated with atherosclerotic plaque progression and to alter plaque morphology towards a stable phenotype.

The role of tumor necrosis factor-like weak inducer of apoptosis in atherosclerosis via its two different receptors

“…The effects of the TWEAK/Fn14 axis on monocytes/macrophages have been supported by several studies (47)(48)(49). By inhibiting the biological function of TWEAK at Fn14 with Fn14-Fc, a study by Schapira et al (47) demonstrated that TWEAK and Fn14 interactions may alter macrophage trafficking and increase lipid uptake of macrophages.…”

“…Additionally, TWEAK was revealed to induce various proinflammatory mediators of atherogenesis, such as IL-6, MCP-1 and IL-8 in activated monocytes (48). There is also evidence that TWEAK is able to enhance MMP-9 and -2 protease activity in apolipoprotein E knockout mice (49).…”

Soluble TWEAK levels predict the presence of carotid atherosclerotic plaques in subjects free from clinical cardiovascular diseases

“…In vitro experiments have demonstrated that TWEAK increases adhesion molecules expression in endothelial cells [34]. TWEAK/Fn14 interaction also augments chemokines expression and secretion by both vascular smooth muscle cells (VSMCs) and macrophages [3,5]. In addition, TWEAK also induces metalloproteinase 3 and 9 activity in both VSMCs and macrophages, favoring plaque instability [5,6].…”

“…TWEAK/Fn14 interaction also augments chemokines expression and secretion by both vascular smooth muscle cells (VSMCs) and macrophages [3,5]. In addition, TWEAK also induces metalloproteinase 3 and 9 activity in both VSMCs and macrophages, favoring plaque instability [5,6]. On the other hand, in vivo experiments have demonstrated that TWEAK participates in development, progression and ultimate rupture of atherosclerotic plaques.…”

“…In addition, Fn14-Fc treatment reduces the size and number of advanced atherosclerotic plaque in ApoE KO mice [4]. Finally, genetic deletion of TWEAK reduces plaque size, inflammatory response and increases plaque stability in ApoE KO mice [5].…”