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. Author manuscript; available in PMC: 2019 Sep 9.
Published in final edited form as: J Mol Cell Cardiol. 2018 Jul 5;121:107–123. doi: 10.1016/j.yjmcc.2018.07.003

Fig. 9.

Fig. 9.

Schema showing a critical role for TRAF3IP2 in TWEAK-induced adverse cardiac remodeling, contractile dysfunction, and heart failure development. TWEAK induced its own expression and that of TWEAKR by inducing TRAF3IP2-dependent p38 MAPK, NF-κB and AP-1 activation, pro-inflammatory and pro-fibrotic cytokin, chemokine, adhesion molecule, and matrix metalloproteinase (MMP) expression, and fibroblast migration and proliferation, resulting in adverse cardiac remodeling, contractile dysfunction, and possible development of heart failure. The membrane localized TWEAK (mTWEAK) is processed by the serine protease furin, resulting in the release of soluble TWEAK (sTWEAK) that forms a homotrimer and binds the TWEAKR to initiate the downstream inflammatory signaling. Notably, TRAF3IP2 deletion blunts these deleterious effects of TWEAK. Arrowheads denote interventions used in delineating the possible signaling pathways activated by TWEAK. Broken arrows: TWEAK has previously been shown to activate MMPs.