Journal Article

PACS2/CPT1A/DHODH signaling promotes cardiomyocyte ferroptosis in diabetic cardiomyopathy

Ouyang, Jie, Zheng, Xinru, Chen, Shuhua, Xiao, Di, Xiang, Hong, Long, HaiJiao, Yang, Xiaoping, Liu, Quanjun, Lu, Hongwei, Lyu, Qi

2024

Overview

Objectives The pathophysiology of diabetic cardiomyopathy (DCM) is a phenomenon of great interest, but its clinical problems have not yet been effectively addressed. Recently, the mechanism of ferroptosis in the pathophysiology of various diseases, including DCM, has attracted widespread attention. Here, we explored the role of PACS2 in ferroptosis in DCM through its downregulation of PACS2 expression. Methods and results Cardiomyocytes were treated with high glucose and palmitic acid (HGPA), and the detection of cardiomyocyte iron ions, lipid peroxides, and reactive oxygen species (ROS) revealed clear ferroptosis during these treatments. Silencing PACS2 downregulated CPT1A expression and upregulated DHODH expression significantly, reversing HGPA-induced ferroptosis. Further silencing of PACS2 with a CPT1A agonist exacerbated cardiomyocyte ferroptosis while promoting mitochondrial damage in cardiomyocytes. Using a mouse model of type 2 diabetes induced by streptozotocin (STZ) and a high-fat diet (HFD), we found that PACS2 deletion reversed these treatment-induced increases in cellular iron ions, impaired cardiac function, mitochondrial damage and ferroptosis in cardiac muscle tissues. Conclusions The PACS2/CPT1A/DHODH signalling pathway may be involved in ferroptosis in DCM by regulating cardiomyocyte mitochondrial function.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Angiology / Animals / Cardiac muscle / Cardiology / Cardiomyocytes / Cardiomyopathy / Carnitine O-Palmitoyltransferase - genetics / Carnitine O-Palmitoyltransferase - metabolism / Cell death / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Experimental - enzymology / Diabetes Mellitus, Type 2 - enzymology / Diabetes Mellitus, Type 2 - genetics / Diabetes Mellitus, Type 2 - metabolism / Diabetic Cardiomyopathies - enzymology / Diabetic Cardiomyopathies - genetics / Diabetic Cardiomyopathies - metabolism / Diabetic Cardiomyopathies - pathology / Diabetic Cardiomyopathies - physiopathology / Diabetic cardiomyopathy / Diet / Diet, High-Fat / Down-regulation / Drinking water / Fatty acids / Ferroptosis / Ferroptosis - drug effects / Glucose / Heart failure / High fat diet / Hyperglycemia / Insulin resistance / Lipids / Male / Medicine / Medicine & Public Health / Metabolic syndrome / Mice / Mice, Inbred C57BL / Mice, Knockout / Mitochondria / Mitochondria, Heart - drug effects / Mitochondria, Heart - enzymology / Mitochondria, Heart - metabolism / Mitochondria, Heart - pathology / Myocytes, Cardiac - drug effects / Myocytes, Cardiac - enzymology / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Oxidation / Palmitic acid / Palmitic Acid - pharmacology / Pathogenesis / Pathophysiology / Proteins / Reactive oxygen species / Reactive Oxygen Species - metabolism / Signal Transduction / Streptozocin