Journal Article

NAT10 induces N4-acetylcytidine modification of AdipoR1-mediated mitochondrial biogenesis against endothelial-to-mesenchymal transition in hypertension

Xu, Zhongqing, Zhou, Jun, Song, Lei, Pan, Huichao, Cheng, Zeyi, Zhu, Jie, Zhang, Min

2025

Overview

Background Endothelial-to-mesenchymal transition (EndMT) in endothelial dysfunction exacerbates hypertension. However, the regulatory mechanisms underlying EndMT in hypertension are yet to be elucidated. Methods The N-acetyltransferase 10 (NAT10) and N4-acetylcytidine (ac4C) levels were determined in hypertensive mice, spontaneously hypertensive rats (SHRs), and angiotensin II (Ang II)-treated human umbilical vein endothelial cells (HUVECs). Biological functional assays were performed with lentiviral vectors to induce the overexpression or knockdown of NAT10 in vivo and in vitro. The detailed mechanisms underlying the role of ac4C-mediated posttranscriptional regulation in hypertension were investigated by combining ac4C-RIP-seq with RNA-seq, RIP-qRCR, mRNA stability, and dual-luciferase assays. Mitochondrial biogenesis and function were assessed via reactive oxygen species (ROS) and mitochondrial ROS (mtROS) staining; estimation of ATP levels, the mitochondrial membrane potential (MMP), and the mtDNA content; and evaluation of mitochondrial respiratory chain complex activities. Results The results revealed that NAT10 and ac4C levels are higher in the hypertensive mice descending thoracic aorta tissues, SHRs descending thoracic aorta samples, and Ang II-treated HUVECs compared to the control groups. NAT10 overexpression inhibits EndMT in hypertension, which is partly due to the inhibition of endothelial dysfunction, whereas NAT10 inhibition has the opposite effect. Mechanistically, NAT10 inhibited endothelial dysfunction in hypertension through increased AdipoR1 mRNA ac4C acetylation. Moreover, NAT10 induced AdipoR1 expression, leading to increased mitochondrial biogenesis and function in Ang II-treated ECs via p38 MAPK/PGC-1α signaling. Conclusions The current data highlighted the molecular mechanisms of NAT10-induced ac4C acetylation and implied that the NAT10-AdipoR1 axis might be the therapeutic target to inhibit endothelial dysfunction and EndMT in hypertension.

• Publisher: BioMed Central,Springer Nature B.V,The Feinstein Institute for Medical Research,BMC
• Subject: Ac4C / Acetylation / Acetyltransferases - genetics / Acetyltransferases - metabolism / AdipoR1 / Angiotensin II / Animals / Biomedical and Life Sciences / Biomedicine / Biosynthesis / Blood pressure / Cardiovascular disease / Coronary vessels / Cytidine - analogs & derivatives / Cytidine - metabolism / DNA methylation / Endothelial cells / Endothelial-to-mesenchymal transition / Epigenetics / Epithelial-Mesenchymal Transition / Experiments / Genotype & phenotype / Human Umbilical Vein Endothelial Cells / Humans / Hypertension / Hypertension - etiology / Hypertension - genetics / Hypertension - metabolism / Hypertension - pathology / Laboratory animals / Male / Mice / Mitochondria - metabolism / Molecular Medicine / NAT10 / Organelle Biogenesis / Pulmonary hypertension / Rats / Rats, Inbred SHR / Reactive Oxygen Species - metabolism / Receptors, Adiponectin - genetics / Receptors, Adiponectin - metabolism / Veins & arteries