6-Gingerol,a pungent ingredient of ginger,has been reported to possess anti-inflammatory and antioxidant activities,but the effect of 6-gingerol on pressure overload-induced cardiac remodeling remains inconclusive.In this study,we investigated the effect of 6-gingerol on cardiac remodeling in in vivo and in vitro models,and to clarify the underlying mechanisms.C57BL/6 mice were subjected to transverse aortic constriction (TAC),and treated with 6-gingerol (20 mg/kg,ig) three times a week(1 week in advance and continued until the end of the experiment).Four weeks after TAC surgery,the mice were subjected to echocardiography,and then sacrificed to harvest the hearts for analysis.For in vitro study,neonatal rat cardiomyocytes and cardiac fibroblasts were used to validate the protective effects of 6-gingerol in response to phenylephrine (PE) and transforming growth factor-β (TGF-β) challenge.We showed that 6-gingerol administration protected against pressure overload-induced cardiac hypertrophy,fibrosis,inflammation,and dysfunction in TAC mice.In the in vitro study,we showed that treatment with 6-gingerol (20 μM) blocked PE-induced-cardiomyocyte hypertrophy and TGF-β-induced cardiac fibroblast activation.Furthermore,6-gingerol treatment significantly decreased mitogen-activated protein kinase p38 (p38) phosphorylation in response to pressure overload in vivo and extracellular stimuli in vitro,which was upregulated in the absence of 6-gingerol treatment.Moreover,transfection with mitogen-activated protein kinase kinase 6 expressing adenoviruses (Ad-MKK6),which specifically activated p38,abolished the protective effects of 6-gingerol in both in vitro and in vivo models.In conclusion,6-gingerol improves cardiac function and alleviates cardiac remodeling induced by pressure overload in a p38-dependent manner.The present study demonstrates that 6-gingerol is a promising agent for the intervention of pathological cardiac remodeling.