Transmembrane tumor necrosis factor alpha attenuates pressure-overload cardiac hypertrophy via tumor necrosis factor receptor 2

• Published in: PLoS biology Vol. 18; no. 12; p. e3000967
• Main Authors: Miao, Kun, Zhou, Ling, Ba, Hongping, Li, Chenxi, Gu, Haiyan, Yin, Bingjiao, Wang, Jing, Yang, Xiang-Ping, Li, Zhuoya, Wang, Dao Wen
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.12.2020; Public Library of Science (PLoS)
• Subjects: Adipocytes; Animals; Antibodies; Aorta; Apoptosis; Apoptosis - drug effects; Atrial natriuretic peptide; Biology and Life Sciences; Body weight; Brain; Brain natriuretic peptide; Cardiac function; Cardiomegaly - metabolism; Cardiomegaly - physiopathology; Cardiomyocytes; Cardiomyopathy; Congestive heart failure; Constrictions; Control; Cytokines; Dehydrogenase; Dehydrogenases; Dosage and administration; Drug therapy; Enzyme-linked immunosorbent assay; Enzymes; Fluorescence; Gene expression; Genetic aspects; Glyceraldehyde; Glyceraldehyde 3-phosphate; Glyceraldehyde-3-phosphate dehydrogenase; Green fluorescent protein; Heart; Heart enlargement; Heart failure; Hypertrophy; Immunofluorescence; Inflammation; Insulin; Interleukin; Interleukins; Ligands; Male; Medical prognosis; Medicine and Health Sciences; Mice; Mice, Inbred BALB C; Mice, Knockout; Mortality; Myocytes, Cardiac - metabolism; Necrosis; NF-kappa B - metabolism; Peptides; Polymerase chain reaction; Pressure; Prognosis; Real time; Receptors; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Receptors, Tumor Necrosis Factor, Type II - genetics; Receptors, Tumor Necrosis Factor, Type II - metabolism; Receptors, Tumor Necrosis Factor, Type II - physiology; Rodents; Sensitizing; Serum levels; Signal Transduction - drug effects; Tumor necrosis factor; Tumor necrosis factor inhibitors; Tumor necrosis factor receptor 2; Tumor necrosis factor receptors; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - physiology; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Ventricle; China
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3000967

Tumor necrosis factor-alpha (TNF-α) 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-α in HF. TNF-α exists in transmembrane (tmTNF-α) and soluble (sTNF-α) 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-α expression, whereas TNFR2 KO or KD exacerbated the pathological phenomena with increased sTNF-α 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-α. Suppressing TNF-α converting enzyme by TNF-α Protease Inhibitor-1 (TAPI-1) to increase endogenous tmTNF-α expression significantly alleviated TAC-induced cardiac hypertrophy. Importantly, direct addition of exogenous tmTNF-α 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-α were completely blocked by TNFR2 KD in H9C2 cells and TNFR2 KO in primary myocardial cells. Furthermore, we demonstrated that tmTNF-α displayed antihypertrophic and anti-inflammatory effects by activating the AKT pathway and inhibiting the nuclear factor (NF)-κB pathway via TNFR2. Our data suggest that tmTNF-α exerts cardioprotective effects via TNFR2. Specific targeting of tmTNF-α processing, rather than anti-TNF therapy, may be more useful for the treatment of hypertrophy and HF.