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.