In summary, our results suggest that tmTNF-α exhibits cardioprotective effects through suppression of NF-κB and activation of the AKT pathway via TNFR2, in contrast to detrimental effects of sTNF-α via TNFR1 in pressure overload–induced cardiac hypertrophy (Fig 8). Here, TNFRSF1A is linked to cardiac hypertrophy.