Lactate regulates pathological cardiac hypertrophy via histone lactylation modification

Under the long‐term pressure overload stimulation, the heart experiences embryonic gene activation, leading to myocardial hypertrophy and ventricular remodelling, which can ultimately result in the development of heart failure. Identifying effective therapeutic targets is crucial for the prevention...

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Vydané v:	Journal of cellular and molecular medicine Ročník 28; číslo 16; s. e70022 - n/a
Hlavní autori:	Zhao, Shuai‐Shuai, Liu, Jinlong, Wu, Qi‐Cai, Zhou, Xue‐Liang
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England John Wiley & Sons, Inc 01.08.2024 John Wiley and Sons Inc
Predmet:	Angiotensin II Animal models Animals Antibodies Cardiac function cardiac hypertrophy Cardiomegaly - metabolism Cardiomegaly - pathology Cardiomyocytes Carotid arteries Cell growth Collagen Congestive heart failure Disease Models, Animal Embryogenesis Environmental effects Epigenetics Gene expression Genetic variability Glucose Glucose - metabolism Glycolysis H3K18la Heart histone lysine lactylation Histones Histones - metabolism HKla Hypertrophy Hypoxia Ischemia Lactic acid Lactic Acid - metabolism Lysine - metabolism Male Metabolism Mice Mice, Inbred C57BL Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Neonates Original Ostomy Phosphorylation post‐translational modification Protein Processing, Post-Translational Surgery Therapeutic targets Veins & arteries United States > US China HKla H3K18la cardiac hypertrophy histone lysine lactylation post‐translational modification
ISSN:	1582-1838, 1582-4934, 1582-4934
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Shrnutí:	Under the long‐term pressure overload stimulation, the heart experiences embryonic gene activation, leading to myocardial hypertrophy and ventricular remodelling, which can ultimately result in the development of heart failure. Identifying effective therapeutic targets is crucial for the prevention and treatment of myocardial hypertrophy. Histone lysine lactylation (HKla) is a novel post‐translational modification that connects cellular metabolism with epigenetic regulation. However, the specific role of HKla in pathological cardiac hypertrophy remains unclear. Our study aims to investigate whether HKla modification plays a pathogenic role in the development of cardiac hypertrophy. The results demonstrate significant expression of HKla in cardiomyocytes derived from an animal model of cardiac hypertrophy induced by transverse aortic constriction surgery, and in neonatal mouse cardiomyocytes stimulated by Ang II. Furthermore, research indicates that HKla is influenced by glucose metabolism and lactate generation, exhibiting significant phenotypic variability in response to various environmental stimuli. In vitro experiments reveal that exogenous lactate and glucose can upregulate the expression of HKla and promote cardiac hypertrophy. Conversely, inhibition of lactate production using glycolysis inhibitor (2‐DG), LDH inhibitor (oxamate) and LDHA inhibitor (GNE‐140) reduces HKla levels and inhibits the development of cardiac hypertrophy. Collectively, these findings establish a pivotal role for H3K18la in pathological cardiac hypertrophy, offering a novel target for the treatment of this condition.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1582-1838 1582-4934 1582-4934
DOI:	10.1111/jcmm.70022