Journal Article

MAP4K4 exacerbates cardiac microvascular injury in diabetes by facilitating S-nitrosylation modification of Drp1

Kong, Xiangqing, Lu, Jian, Wang, Jiankang, Yan, Xiaopei, Guan, Bo, Du, Yingqiang, Chen, Yuqiong, Chen, Zhangwei, Yang, Fan, Chen, Chao, Huang, Chao, Zhang, Nannan, Li, Yafei, Zhang, Jun, Li, Su

2024

Overview

Dynamin-related protein 1 (Drp1) is a crucial regulator of mitochondrial dynamics, the overactivation of which can lead to cardiovascular disease. Multiple distinct posttranscriptional modifications of Drp1 have been reported, among which S-nitrosylation was recently introduced. However, the detailed regulatory mechanism of S-nitrosylation of Drp1 (SNO-Drp1) in cardiac microvascular dysfunction in diabetes remains elusive. The present study revealed that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was consistently upregulated in diabetic cardiomyopathy (DCM) and promoted SNO-Drp1 in cardiac microvascular endothelial cells (CMECs), which in turn led to mitochondrial dysfunction and cardiac microvascular disorder. Further studies confirmed that MAP4K4 promoted SNO-Drp1 at human C644 (mouse C650) by inhibiting glutathione peroxidase 4 (GPX4) expression, through which MAP4K4 stimulated endothelial ferroptosis in diabetes. In contrast, inhibition of MAP4K4 via DMX-5804 significantly reduced endothelial ferroptosis, alleviated cardiac microvascular dysfunction and improved cardiac dysfunction in db/db mice by reducing SNO-Drp1. In parallel, the C650A mutation in mice abolished SNO-Drp1 and the role of Drp1 in promoting cardiac microvascular disorder and cardiac dysfunction. In conclusion, our findings demonstrate that MAP4K4 plays an important role in endothelial dysfunction in DCM and reveal that SNO-Drp1 and ferroptosis activation may act as downstream targets, representing potential therapeutic targets for DCM.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Angiogenesis / Angiology / Animals / Cardiac microvascular injury / Cardiology / Cardiomyocytes / Cardiomyopathy / Cardiovascular diseases / Cells, Cultured / Coronary Circulation / Diabetes / Diabetes mellitus / Diabetic Cardiomyopathies - enzymology / Diabetic Cardiomyopathies - etiology / Diabetic Cardiomyopathies - genetics / Diabetic Cardiomyopathies - metabolism / Diabetic Cardiomyopathies - pathology / Diabetic Cardiomyopathies - physiopathology / Diabetic cardiomyopathy / Disease Models, Animal / Drp1 / Dynamin / Dynamins - genetics / Dynamins - metabolism / Endothelial cells / Endothelial Cells - drug effects / Endothelial Cells - enzymology / Endothelial Cells - metabolism / Endothelial Cells - pathology / Endothelium / Ferroptosis / Ferroptosis - drug effects / Glutathione peroxidase / Health risks / Heart / Humans / Inflammation and Cardiometabolic Disease / Intracellular Signaling Peptides and Proteins / Kinases / Laboratory animals / Lectins / Lipids / Male / MAP kinase / MAP4K4 / Medicine / Medicine & Public Health / Mice / Microvasculature / Mitochondria, Heart - enzymology / Mitochondria, Heart - metabolism / Mitochondria, Heart - pathology / Morphology / Mutation / Permeability / Post-transcription / Protein Processing, Post-Translational / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteins / S-nitrosylation / Signal Transduction / Software / Therapeutic targets / Therapy / Veins & arteries