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

Abstract

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK/Tnfsf12) is a cytokine implicated in different steps associated with vascular remodeling. However, the role of TWEAK under hyperglycemic conditions is currently unknown. Using two different approaches, genetic deletion of Tnfsf12 and treatment with a TWEAK blocking mAb, we have analyzed the effect of TWEAK inhibition on atherosclerotic plaque progression and stability in streptozotocin-induced diabetic ApoE deficient mice. Genetic inactivation of Tnfsf12 reduced atherosclerosis extension and severity in diabetic ApoE deficient mice. Tnfsf12 deficient mice display a more stable plaque phenotype characterized by lower lipid and macrophage content within atherosclerotic plaques. A similar phenotype was observed in diabetic mice treated with anti-TWEAK mAb. The proatherosclerotic effects of TWEAK were mediated, at least in part, by STAT1 activation and expression of proinflammatory target genes (CCL5, CXCL10 and ICAM-1), both in plaques of ApoE mice and in cultured vascular smooth muscle cells (VSMCs) under hyperglycemic conditions. Loss-of-function experiments demonstrated that TWEAK induces proinflammatory genes mRNA expression through its receptor Fn14 and STAT1 activation in cultured VSMCs. Overall, TWEAK blockade delay plaque progression and alter plaque composition in diabetic atherosclerotic mice. Therapies aimed to inhibit TWEAK expression and/or function could protect from diabetic vascular complications.

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK)/Fibroblast Growth Factor-Inducible 14 (Fn14) Axis in Cardiovascular Diseases: Progress and Challenges

“…In this sense, treatment of SMCs with rTWEAK favors the vascular phenotypic switching, increasing osteopontin and decreasing α -actin and calponin gene expression. Moreover, the number of osteopontin positive SMCs increases in atherosclerotic plaques from TWEAK/ Apolipoprotein E (ApoE) double deficient mice, confirming the role of TWEAK on SMCs phenotypic changes in vivo [39]. Both, inflammatory cells and SMCs favor plaque progression by increasing cytokines and MMPs expression.…”

“…This trimeric structure induces the recruitment of TRAF2 and TRAF5 though the TRAF-binding motif (PIEET) in the cytoplasmic tail, and leads the activation of different signaling pathways [14,35]. TWEAK-Fn14 binding activates several signal transduction pathways that implicate both canonical and non-canonical NF-kB pathways [14,36], mitogen-activated protein kinases pathway (MAPK) [37], PI3K/AKT [38], JAK/STAT signaling pathway [39,40], and transforming growth factor-β-activated kinase 1 [41]. MAPK activation induced by recombinant soluble TWEAK (rTWEAK) has been reported in endothelial cells [33], Thp-1 monocytic cell line [26], and cardiomyocytes [30].…”

“…In addition, genetic deletion of TWEAK or anti-TWEAK Monoclonal antibody (mAb) treatment decreases CCL2 and CCL5 protein expression in atherosclerotic plaques, and increases features of plaque stability in hyperlipidemic ApoE deficient mice [65]. Recombinant TWEAK injection also increases inflammation in a model of atherosclerosis progression under high-glucose conditions (streptozotocin-induced diabetic ApoE deficient mice) [39]. In vitro loss-of-function experiments in cultured SMCs, in vivo inhibition of TWEAK by genetic deletion, or pharmacological intervention showed that TWEAK regulates CCL5, CXCL10, and ICAM-1 mRNA expression through Signal Transducer and Activator of Transcription 1 (STAT-1) phosphorylation [39].…”

“…Recombinant TWEAK injection also increases inflammation in a model of atherosclerosis progression under high-glucose conditions (streptozotocin-induced diabetic ApoE deficient mice) [39]. In vitro loss-of-function experiments in cultured SMCs, in vivo inhibition of TWEAK by genetic deletion, or pharmacological intervention showed that TWEAK regulates CCL5, CXCL10, and ICAM-1 mRNA expression through Signal Transducer and Activator of Transcription 1 (STAT-1) phosphorylation [39].…”

A novel Tweak/ Stat1/ Snhg3 positive feedback circuit contributes to the glial cell activation in temporal lobe epilepsy mice

“…STAT1 is a member of the STATs protein family and is composed of seven potential cytoplasmic transcription factors that play key roles in different physiological functions including apoptosis, cell survival, immune response, and proliferation [18]. It has been demonstrated that TWEAK induces proinflammatory genes mRNA expression through its receptor Fn14 and STAT1 activation in cultured vascular smooth muscle cells [19]. Researches have shown that LncRNA H19 contributes to hippocampal glial cell activation via JAK/STAT signaling in a rat model of temporal lobe epilepsy [20].…”