Protein acylation and heart failure: A review of novel lysine modifications in cardiac pathology

Table 1 Summary of classical lysine acetylation in pathological cardiac hypertrophy and heart failure

Typical lysine acylation	Models	Sites	Specific functions	Refs.
Acetylation	Mice	H3K4ac, H3K9ac, H3K27ac	H3K4ac, H3K9ac, and H3K27ac mediated by p300 are increased in cardiac hypertrophy and HF	[24,25]
Acetylation	Mice	H3K27ac	H3K27ac mediated by p300 exacerbates cardiac dysfunction	[26]
Acetylation	Mice	H3K9ac; H3K23ac	H3K23ac and H3K9ac are elevated in hearts of mice with diabetic cardiomyopathy	[27]
Acetylation	Mice	K3K14ac	H3K14ac is increased in mice induced by prenatal alcohol exposure, which contributed to abnormal fetal heart development	[28]
Acetylation	Rats	H3K122ac	H3K122ac is increased during the stages of HF	[29]
Acetylation	Mice, human	SERCA2a K492ac	Increased SERCA2a K492ac is associated with systolic dysfunction in HF	[30]
Acetylation	Mice	TFAM (K62ac, K76ac, K111ac, K118ac)	Acetylation of TFAM 4KR is diminished in response to low expression of GCN 5 L 1 in HF, which results in a reduction in mitochondrial DNA abundance and impaired cardiac energetics	[31]
Acetylation	Mice	P53 4KR (k98ac, K117ac, K161ac, K162ac)	Increased P53 4KR acetylation leads to coronary capillary sparsity, cardiac remodeling, and cardiac dysfunction	[32]
Acetylation	Mice	P53 K381ac	Lipopolysaccharide increases p53 K381ac and promotes the nuclear translocation of p53, contributing to cardiac dysfunction	[33]
Acetylation	Mice	Drp1 K642ac	High-fat diet leads to DRP1 K642ac increase, which activates DRP1 and results in cardiomyocyte dysfunction and death	[34]
Acetylation	Mice	SF3A2 K10ac	Ginsenoside Rb2 directly interacts with P300 to reduce SF3A2 K10ac, enhance mitochondrial respiration, and mitigate cardiac dysfunction	[35]

DRP1: Dynamin-related protein 1; HF: Heart failure; SERCA2a: Sarco/endoplasmic reticulum calcium ATPase 2a; TFAM: Mitochondrial transcription factor A.

Table 2 Summary of novel lysine acylations and pathological cardiac hypertrophy and heart failure

Novel lysine acylations	Models	Sites	Specific functions	Refs.
Crotonylation	Mice	TMP1 K28/29cr; IDH3α K199cr	TMP1 K28/29 and IDH3α K199cr are decreased in a model of cardiac dysfunction induced by ischemia-reperfusion	[53]
Crotonylation	Human; mice	H3K18cr, H2BK12cr	H3K18cr and H2BK12cr are elevated in hypertrophic cardiomyopathy	[54]
Crotonylation	Mice	NAE1 K238cr	NAE1 K238cr increases in the cardiac hypertrophy model	[55]
Crotonylation	Mice	SERCA2a K120cr	SERCA2a K120cr is significantly elevated in SIRT1 knockout mice, which impairs SERCA2a activity and leads to alterations in energy metabolism that precipitate cardiac hypertrophy and dysfunction	[56]
Lactylation	Mice	α-MHC K1897 La	α-MHC K1897 La reduction in heart failure weakens its interaction with titin, ultimately resulting in severe HF	[48]
Lactylation	Mice	H3K18 La	The elevation of H3K18 La is associated with pathological myocardial hypertrophy and cardiac dysfunction	[59]
Lactylation	Mice	H3K56 La	H3K56 La is reduced in the Mi/R model, and the inhibition of H3K56 La negated the cardioprotective effects of HSPA12A	[60]
Lactylation	Mice	H3K18 La	Exercise training enhances cardiac function by inhibiting YTHDF2, which reduces H3K18 lactylation and mitigates myocardial ischemia-reperfusion injury	[61]
Lactylation	Mice	Snail1	The lactylation of Snail1 was elevated following myocardial infarction, which contributed to myocardial fibrosis and worsened cardiac dysfunction	[62]
Succinylation	Mice	ECHA K351succ	SIRT5 mediates the desuccinylation of ECHA K351, thereby improving cardiac metabolism and function and reducing myocardial hypertrophy	[71]
Succinylation	Mice	IDH2	The inhibition of SIRT5 expression results in increased succinylation of IDH2, which disrupts mitochondrial homeostasis and contributes to myocardial fibrosis and HF	[72]
Succinylation	Human; mice	CPT2 K424succ	SIRT5 mediates the desuccinylation of CPT2 K424 in diabetic cardiomyopathy, thereby ameliorating lipid deposition, myocardial hypertrophy, and diastolic dysfunction	[73]
Succinylation	Mice	Txnrd1 K534succ	Txnrd1 K534succ increase in mice with a knockout of LDHA, leading to severe cardiac dysfunction in a pressure overload mouse model	[74]
β-hydroxybutyr-ylation	Mice	CS K395bhb	β-hydroxybutyrate mitigates heart failure with preserved ejection fraction by activating CS through the enhancement of CS K395bhb	[82]
Propionylation	Mice	H3K23pr	H3K23pr increase in cardiac hypertrophy and HF	[86]
Butyrylation	Mice	H3K9bu	H3K9bu is diminished due to the downregulation of β-oxidase in the heart following TAC surgery	[90]
Malonylation	Rat	VDAC2 K46mal	VDAC2 K46mal was elevated in mice with sepsis-induced cardiac dysfunction	[97]
Malonylation	Mice	GSTP1 K121mal	The abnormal decrease of SIRT5 increase of GSTP1 K121mal in DCM leads to oxidative stress and mitochondrial dysfunction	[98]
Malonylation	Mice	Ago2 K440mal	The increase of AGO2 K440mal enhances the production of ROS in mitochondria, subsequently impairing cardiac function in DCM	[99]
2-hydroxyisobu-tyrylation	Mice	DLD K440hib	DLD K440hib increase in the TAC-induced cardiac hypertrophy model	[105]

AGO2: Argonaute 2; CPT2: Carnitine palmitoyltransferase 2; CS: Citrate synthase; DCM: Diabetic cardiomyopathy; ECHA: E-CoA hydratase α subunit; GSTP1: Glutathione S-transferase 1; HF: Heart failure; HSPA12A: Heat shock protein family A member 12A; IDH: Isocitrate dehydrogenase; LDHA: Lactate dehydrogenase A; α-MHC: Α-myosin heavy chain; NAE1: NEDD8-activating enzyme E1 regulatory subunit; ROS: Reactive oxygen species; SERCA2a: Sarco/endoplasmic reticulum calcium ATPase 2a; SIRT: Sirtuin; Txnrd1: Thioredoxin reductase 1; VDAC2: Voltage-dependent anion-selective channel protein 2; YTHDF2: YT521-B homology domain family member 2; TAC: Transverse aortic constriction.