Tumor Necrosis Factor‐Like Weak Inducer of Apoptosis or Fn14 Deficiency Reduce Elastase Perfusion‐Induced Aortic Abdominal Aneurysm in Mice

Abstract

BackgroundAbdominal aortic aneurysm (AAA) involves leukocyte recruitment, inflammatory cytokine production, vascular cell apoptosis, neovascularization, and vascular remodeling, all of which contribute to aortic dilatation. Tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) is a cytokine implicated in proinflammatory responses, angiogenesis, and matrix degradation but its role in AAA formation is currently unknown.Methods and ResultsExperimental AAA with aortic elastase perfusion in mice was induced in wild‐type (WT), TWEAK deficient (TWEAK KO), or Fn14‐deficient (Fn14 KO) mice. TWEAK or Fn14 KO deficiency reduced aortic expansion, lesion macrophages, CD3+ T cells, neutrophils, CD31+ microvessels, CCL2 and CCL5 chemokines expression, and MMP activity after 14 days postperfusion. TWEAK and Fn14 KO mice also showed a reduced loss of medial vascular smooth muscle cells (VSMC) that was related to a reduced number of apoptotic cells in these animals compared with WT mice. Aortas from WT animals present a higher disruption of the elastic layer and MMP activity than those from TWEAK or Fn14 KO mice, indicating a diminished vascular remodeling in KO animals. In vitro experiments unveiled that TWEAK induces CCL5 secretion and MMP‐9 activation in both VSMC and bone marrow‐derived macrophages, and decrease VSMC viability, effects dependent on Fn14.ConclusionsTWEAK/Fn14 axis participates in AAA formation by promoting lesion inflammatory cell accumulation, angiogenesis, matrix‐degrading protease expression, and vascular remodeling. Blocking TWEAK/Fn14 interaction could be a new target for the treatment of AAA.

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

“…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.…”

“…TWEAK/Fn14 interaction could participate in different processes associated with atherosclerotic plaque development such as proliferation and migration of vascular cells, and angiogenesis, inflammation and thrombosis. In fact, experimental studies have demonstrated that TWEAK participates in atherosclerotic plaque development, progression and rupture [3e5], and contributes to susceptibility for developing abdominal aortic aneurysm [6]. In addition, persistent TWEAK/Fn14 activation/ inactivation mediated by blocking or overexpression experiments in animal models has shown an important role of this axis in several pathologies such as stroke, heart failure and myocardial infarction, among others [7e9].…”

Soluble TWEAK and Major Adverse Cardiovascular Events in Patients with CKD

“…Experimental studies have shown a key role of the TWEAK-Fn14 axis in atherosclerotic plaque development, progression, and rupture (5-7). Moreover, specific gain-or loss-of-function phenotypes have shown that TWEAK participates in the development of experimental abdominal aortic aneurysms, stroke, myocardial infarction, and heart failure (8)(9)(10)(11).…”

TWEAK blockade decreases atherosclerotic lesion size and progression through suppression of STAT1 signaling in diabetic mice

“…In the arterial wall, TWEAK is expressed in both healthy arteries and atherosclerotic plaques10. However, Fn14 expression is low or absent in normal arteries but is highly upregulated under pathological conditions including atherosclerotic plaques and abdominal aortic aneurysm of both, murine and human origin10111213. TWEAK is involved in different steps associated with vascular remodeling such as endothelial dysfunction, inflammation, proliferation and migration of VSMCs, angiogenesis and thrombosis141516.…”