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TNF-\u03b1 exists in transmembrane (tmTNF-\u03b1) and soluble (sTNF-\u03b1) 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-\u03b1 expression, whereas TNFR2 KO or KD exacerbated the pathological phenomena with increased sTNF-\u03b1 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-\u03b1. Suppressing TNF-\u03b1 converting enzyme by TNF-\u03b1 Protease Inhibitor-1 (TAPI-1) to increase endogenous tmTNF-\u03b1 expression significantly alleviated TAC-induced cardiac hypertrophy. Importantly, direct addition of exogenous tmTNF-\u03b1 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-\u03b1 were completely blocked by TNFR2 KD in H9C2 cells and TNFR2 KO in primary myocardial cells. Furthermore, we demonstrated that tmTNF-\u03b1 displayed antihypertrophic and anti-inflammatory effects by activating the AKT pathway and inhibiting the nuclear factor (NF)-\u03baB pathway via TNFR2. Our data suggest that tmTNF-\u03b1 exerts cardioprotective effects via TNFR2. Specific targeting of tmTNF-\u03b1 processing, rather than anti-TNF therapy, may be more useful for the treatment of hypertrophy and HF.<\/jats:p>","DOI":"10.1371\/journal.pbio.3000967","type":"journal-article","created":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T18:27:54Z","timestamp":1607020074000},"page":"e3000967","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":40,"title":["Transmembrane tumor necrosis factor alpha attenuates pressure-overload cardiac hypertrophy via tumor necrosis factor receptor 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