Interactions between the ERK1/2 signaling pathway and PCAF play a key role in PE‑induced cardiomyocyte hypertrophy

Abstract

Cardiomyocyte hypertrophy is a compensatory phase of chronic heart failure that is induced by the activation of multiple signaling pathways. The extracellular signal-regulated protein kinase (ERK) signaling pathway is an important regulator of cardiomyocyte hypertrophy. In our previous study, it was demonstrated that phenylephrine (PE)-induced cardiomyocyte hypertrophy involves the hyperacetylation of histone H3K9ac by P300/CBP-associated factor (PCAF). However, the upstream signaling pathway has yet to be fully identified. In the present study, the role of the extracellular signal-regulated protein kinase (ERK)1/2 signaling pathway in PE-induced cardiomyocyte hypertrophy was investigated. The mice cardiomyocyte hypertrophy model was successfully established by treating cells with PE in vitro. The results showed that phospho-(p-)ERK1/2 interacted with PCAF and modified the pattern of histone H3K9ac acetylation. An ERK inhibitor (U0126) and/or a histone acetylase inhibitor (anacardic acid; AA) attenuated the overexpression of phospho-ERK1/2 and H3K9ac hyperacetylation by inhibiting the expression of PCAF in PE-induced cardiomyocyte hypertrophy. Moreover, U0126 and/or AA could attenuate the overexpression of several biomarker genes related to cardiac hypertrophy (myocyte enhancer factor 2C, atrial natriuretic peptide, brain natriuretic peptide and β-myosin heavy chain) and prevented cardiomyocyte hypertrophy. These results revealed a novel mechanism in that AA protects against PE-induced cardiomyocyte hypertrophy in mice via the ERK1/2 signaling pathway, and by modifying the acetylation of H3K9ac. These findings may assist in the development of novel methods for preventing and treating hypertrophic cardiomyopathy.

Pharmacological inhibition of the acetyltransferase Tip60 mitigates myocardial infarction injury

“…As shown in Table S1, several drugs are available that inhibit the conserved acetyltransferase domain shared by the ∼20 members (Voss and Thomas, 2018) of the KAT family. Among these, anacardic acid (Peng et al, 2015;Li et al, 2019b;Mao et al, 2021), MG149 (Yu et al, 2018), C646 (Rai et al, 2019;Su et al, 2020), garcinol (Balasubramanyam et al, 2004;Li et al, 2020b) and curcumin (Morimoto et al, 2008;González-Salazar et al, 2011;Yang et al, 2013;Sunagawa et al, 2014;Xiao et al, 2016;Sunagawa et al, 2018;Li et al, 2020a)all of which nonselectively target acetyltransferase domains in KATshave been reported to limit dysfunction caused by cardiac ischemia and hypertrophy. Among these, the polyphenol curcumin, which inhibits p300 [Kat3b; also known as EP300; half-maximal inhibitory concentration (IC 50 ) ∼40 µM] with reasonable selectivity (Wu et al, 2009) in comparison with Tip60 (IC 50 ∼200 µM), has received most attention, resulting in improved cardiac function in preclinical and clinical studies (reviewed in Li et al, 2020a).…”

Mitigation of Injury from Myocardial Infarction by TH1834, an Inhibitor of the Acetyltransferase Tip60

“…As tabulated in Figure 1A, several drugs are available that inhibit the conserved acetyltransferase domain shared by the ~20 members [24] of the KAT family. Among these, anacardic acid [25][26][27], MG149 [28], C646 [29,30], garcinol [31,32], and curcumin [33][34][35][36][37][38][39] -all of which nonselectively target acetyltransferase domains in KATs -have been reported to limit dysfunction caused by cardiac ischemia and hypertrophy. Among these, the polyphenol curcumin, which inhibits p300 (Kat3b; IC 50 ~40 µM) with reasonable selectivity [40] in comparison with Tip60 (IC50 ~200 µM), has received most attention, resulting in improved cardiac function in pre-clinical and clinical studies (review, [39]).…”

Roles of histone acetylation sites in cardiac hypertrophy and heart failure

“…Hypertrophic stress increases HAT activity and histone acetylation, as p300 is regulated by several proteins, including ERK1/2, Akt, and Cdk9 ( 3 ). However, for HATs such as GCN5, CBP, and PCAF, the relationship with histone acetylation is unclear, although an association between cardiac hypertrophy and heart failure has been reported ( 48 – 50 ).Curcumin, a natural product, inhibits histone acetylation by blocking the HAT activity of p300, thereby improving cardiomyocyte hypertrophy and HF ( 32 ). Curcumin has also been reported to inhibit heart failure with preserved ejection fraction in Dahl rats ( 47 ).…”