Transmembrane tumor necrosis factor alpha attenuates pressure-overload cardiac hypertrophy via tumor necrosis factor receptor 2
Open Access
- 1 December 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Biology
- Vol. 18 (12), e3000967
- https://doi.org/10.1371/journal.pbio.3000967
Abstract
Tumor necrosis factor-alpha (TNF-alpha) plays an important pathogenic role in cardiac hypertrophy and heart failure (HF); however, anti-TNF is paradoxically negative in clinical trials and even worsens HF, indicating a possible protective role of TNF-alpha in HF. TNF-alpha exists in transmembrane (tmTNF-alpha) and soluble (sTNF-alpha) forms. Herein, we found that TNF receptor 1 (TNFR1) knockout (KO) or knockdown (KD) by short hairpin RNA or small interfering RNA (siRNA) significantly alleviated cardiac hypertrophy, heart dysfunction, fibrosis, and inflammation with increased tmTNF-alpha expression, whereas TNFR2 KO or KD exacerbated the pathological phenomena with increased sTNF-alpha secretion in transverse aortic constriction (TAC)- and isoproterenol (ISO)-induced cardiac hypertrophy in vivo and in vitro, respectively, indicating the beneficial effects of TNFR2 associated with tmTNF-alpha. Suppressing TNF-alpha converting enzyme by TNF-alpha Protease Inhibitor-1 (TAPI-1) to increase endogenous tmTNF-alpha expression significantly alleviated TAC-induced cardiac hypertrophy. Importantly, direct addition of exogenous tmTNF-alpha into cardiomyocytes in vitro significantly reduced ISO-induced cardiac hypertrophy and transcription of the pro-inflammatory cytokines and induced proliferation. The beneficial effects of tmTNF-alpha were completely blocked by TNFR2 KD in H9C2 cells and TNFR2 KO in primary myocardial cells. Furthermore, we demonstrated that tmTNF-alpha displayed antihypertrophic and anti-inflammatory effects by activating the AKT pathway and inhibiting the nuclear factor (NF)-kappa B pathway via TNFR2. Our data suggest that tmTNF-alpha exerts cardioprotective effects via TNFR2. Specific targeting of tmTNF-alpha processing, rather than anti-TNF therapy, may be more useful for the treatment of hypertrophy and HF.Keywords
Funding Information
- National Natural Science Foundation of China (81471899)
- National Natural Science Foundation of China (3167080495)
- National Natural Science Foundation of China (81800335)
- National Natural Science Foundation of China (81800355)
- Fundamental Research Funds for the Central Universities (No. 2015ZDTD044)
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