Anacardic acid attenuates myocardial fibrosis through inhibiting histone H4K16ac hyperacetylation mediated by KAT8 in TAC mice

Abstract:

Objective To explore the histone acetylation mechanism of histone acetylases（HATs） to inhibit anacardic acid（AA） attenuating myocardial fibrosis in thoracic aortic constriction（TAC） mice， and provide a new target for the prevention and treatment of myocardial fibrosis.Methods SPF grade Kunming mice of 6-8 weeks were selected as the research animals and randomly divided into five groups：Normal group，Sham group，TAC group，TAC+Vehicle（TAC+Veh） group，and TAC+AA group. TAC mice models were detected by echocardiography in 12 weeks after TAC，and myocardial tissues of mice were collected for analysis. The cardiac morphology and myocardial fibrosis were observed by Masson staining. The expression of KAT8，H4K16ac，TGF-β1，SMAD3，Collagen Ⅰ， and Collagen Ⅲ were assayed by Western blot. The interaction between KAT8 and H4K16ac was detected by co-immunoprecipitation（Co-IP）.Results Echocardiography showed that TAC model mice were successfully constructed. The results of Masson staining showed that the hearts of mice in TAC group were enlarged，collagen deposition in myocardial tissues increased and fibrosis was obvious compared with that in Sham group，while the hearts of mice in TAC+AA group were smaller，collagen deposition in myocardial tissues decreased and fibrosis degree was lighter than that in TAC group. Western blot results showed that the expression of KAT8 and H4K16ac in myocardial tissues of mice in TAC group were significantly higher than those in Sham group（all P<0.05）. And the protein expression levels of TGF-β1，SMAD3，Collagen Ⅰ and Collagen Ⅲ were significantly higher than those of Sham group（all P<0.05）. Compared with TAC group，AA significantly inhibited the overexpression of KAT8 and the hyperacetylation of H4K16ac in TAC mice（all P<0.05）. Meanwhile，the protein expression levels of TGF-β1，SMAD3，CollagenⅠand Collagen Ⅲ in TAC+AA group were significantly decreased compared with TAC group（all P<0.05）. The Co-IP results showed that KAT8 could bind to H4K16ac. In addition，AA significantly improved the survival rate of TAC mice.Conclusion KAT8-mediated hyperacetylation of H4K16ac may be involved in myocardial fibrosis in TAC mice by regulating TGF-β1/SMAD3 signaling pathway，while AA could attenuate myocardial fibrosis in TAC mice by inhibiting KAT8-mediated hyperacetylation of histone H4K16ac.