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TRAF3 Interacting Protein 2 (TRAF3IP2) Expression is Increased in Failing Human Hearts of Ischemic Origin and Mediates the Pro‐fibrotic Responses of Transforming Growth Factor‐β (TGF‐β) in Adult Human Cardiac Fibroblasts
Author(s) -
Russell Jacob,
Mummidi Srinivas,
Day Sharlene,
Sukhanov Sergiy,
Bender Shawn,
Chandrasekar Bysani
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03872
Subject(s) - ctgf , fibrosis , blot , growth factor , transforming growth factor , biology , proinflammatory cytokine , medicine , inflammation , endocrinology , cancer research , receptor , biochemistry , gene
Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Chronic inflammation contributes to HF development and progression. We have previously demonstrated the causal role and the therapeutic potential of targeting TRAF3IP2, a proinflammatory cytoplasmic adapter molecule, in ischemia/reperfusion‐induced adverse myocardial remodeling and heart failure development in a mouse model. However, it is not known whether failing human hearts of ischemic origin express increased TRAF3IP2. Therefore, we hypothesized that TRAF3IP2 expression is increased during human HF of ischemic origin and investigated the molecular mechanisms underlying the induction and role of TRAF3IP2 in TGF‐β‐induced pro‐fibrotic responses in cultured primary human cardiac fibroblasts (CF). The expression of TRAF3IP2 and its downstream signaling intermediates were analyzed in left ventricular (LV) tissue from explanted human hearts (failing human hearts of ischemic origin, HF‐I) of both sexes, with LV tissue from non‐failing (NF) human donor hearts deemed unsuitable for transplantation serving as controls. The data show that HF‐I is characterized by myocardial hypertrophy, fibrosis (Picrosirius Red staining), contractile dysfunction (echocardiography), increased TRAF3IP2 expression (Western blotting and immunofluorescence), activation of Nuclear Factor Kappa B (NF‐κB, phospho‐p65), Activator Protein 1 (AP‐1, phospho‐c‐Jun), and p38 Mitogen‐Activated Protein Kinase (p38 MAPK, phospho‐p38) (Western blotting using activation‐specific antibodies), and enhanced expression of pro‐inflammatory and pro‐fibrotic mediators Interleukin‐6 (IL‐6), IL‐17A, IL‐18, Connective Tissue Growth Factor (CTGF) (RT‐qPCR), collagens I and III, lysyl oxidase, Matrix Metalloproteinases (MMPs) (Western blotting), and TGF‐β (functional assay). In cultured CF, TGF‐β induced TRAF3IP2 expression in part via AP‐1, and induced TRAF3IP2‐dependent inflammatory cytokine expression, MMP2/9 activation, collagen expression, and migration (Boyden chamber assay) and proliferation (CyQuant assay). Moreover, forced expression of TRAF3IP2 by itself induced TGF‐β expression. These data suggest that TRAF3IP2 plays a causal role in the development and progression of heart failure, and may be a therapeutic target.