PMID- 33270628 OWN - NLM STAT- MEDLINE DCOM- 20210202 LR - 20210202 IS - 1545-7885 (Electronic) IS - 1544-9173 (Print) IS - 1544-9173 (Linking) VI - 18 IP - 12 DP - 2020 Dec TI - Transmembrane tumor necrosis factor alpha attenuates pressure-overload cardiac hypertrophy via tumor necrosis factor receptor 2. PG - e3000967 LID - 10.1371/journal.pbio.3000967 [doi] LID - e3000967 AB - 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)-kappaB 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. FAU - Miao, Kun AU - Miao K AD - Division of Cardiology, Department of Internal Medicine and Department of Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Zhou, Ling AU - Zhou L AD - Division of Cardiology, Department of Internal Medicine and Department of Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Ba, Hongping AU - Ba H AD - Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Li, Chenxi AU - Li C AD - Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Gu, Haiyan AU - Gu H AD - Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Yin, Bingjiao AU - Yin B AD - Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Wang, Jing AU - Wang J AD - Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Yang, Xiang-Ping AU - Yang XP AD - Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Li, Zhuoya AU - Li Z AD - Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Wang, Dao Wen AU - Wang DW AUID- ORCID: 0000-0002-9774-3980 AD - Division of Cardiology, Department of Internal Medicine and Department of Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201203 PL - United States TA - PLoS Biol JT - PLoS biology JID - 101183755 RN - 0 (NF-kappa B) RN - 0 (Receptors, Tumor Necrosis Factor, Type I) RN - 0 (Receptors, Tumor Necrosis Factor, Type II) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM CIN - PLoS Biol. 2020 Dec 9;18(12):e3001037. PMID: 33296366 MH - Animals MH - Apoptosis/drug effects MH - Cardiomegaly/*metabolism/physiopathology MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Mice, Knockout MH - Myocytes, Cardiac/metabolism MH - NF-kappa B/metabolism MH - Receptors, Tumor Necrosis Factor, Type I/genetics/metabolism MH - Receptors, Tumor Necrosis Factor, Type II/genetics/*metabolism/physiology MH - Signal Transduction/drug effects MH - Tumor Necrosis Factor-alpha/*metabolism/physiology PMC - PMC7714153 COIS- The authors have declared that no competing interests exist. EDAT- 2020/12/04 06:00 MHDA- 2021/02/03 06:00 PMCR- 2020/12/03 CRDT- 2020/12/03 17:14 PHST- 2019/08/10 00:00 [received] PHST- 2020/10/23 00:00 [accepted] PHST- 2020/12/03 17:14 [entrez] PHST- 2020/12/04 06:00 [pubmed] PHST- 2021/02/03 06:00 [medline] PHST- 2020/12/03 00:00 [pmc-release] AID - PBIOLOGY-D-19-02339 [pii] AID - 10.1371/journal.pbio.3000967 [doi] PST - epublish SO - PLoS Biol. 2020 Dec 3;18(12):e3000967. doi: 10.1371/journal.pbio.3000967. eCollection 2020 Dec.