In the present study, we demonstrated, for the first time, that tmTNF-α was a major ligand for TNFR2-mediated cardioprotective effects because tmTNF-α expression was increased by TNFR1 KD/KO, and addition of exogenous tmTNF-α attenuated pressure overload–induced cardiac hypertrophy and inflammation through activation of AKT and inhibition of NF-κB via TNFR2. The gene discussed is TNFRSF1B; the disease is cardiac hypertrophy.