Laboratory of Heart Valve Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Laboratory of Heart Valve Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Jun;1870(5):167158. doi: 10.1016/j.bbadis.2024.167158. Epub 2024 Apr 6.
Diabetic cardiomyopathy (DCM) is the leading cause of mortality in type 2 diabetes mellitus (T2DM) patients, with its underlying mechanisms still elusive. This study aims to investigate the role of cholesterol-25-monooxygenase (CH25H) in T2DM induced cardiomyopathy.
High fat diet combined with streptozotocin (HFD/STZ) were used to establish a T2DM model. CH25H and its product 25-hydroxycholesterol (25HC) were detected in the hearts of T2DM model. Gain- or loss-of-function of CH25H were performed by receiving AAV9-cTNT-CH25H or CH25H knockout (CH25H) mice with HFD/STZ treatment. Cardiac function was evaluated using echocardiography, and cardiac tissues were collected for immunoblot analysis, histological assessment and quantitative polymerase chain reaction (qPCR). Mitochondrial morphology and function were evaluated using transmission electron microscopy (TEM) and Seahorse XF Cell Mito Stress Test Kit. RNA-sequence analysis was performed to determine the molecular changes associated with CH25H deletion.
CH25H and 25HC were significantly decreased in the hearts of T2DM mice. CH25H mice treated with HFD/STZ exhibited impaired mitochondrial function and structure, increased lipid accumulation, and aggregated cardiac dysfunction. Conversely, T2DM mice receiving AAV9-CH25H displayed cardioprotective effects. Mechanistically, RNA sequencing and qPCR analysis revealed that CH25H deficiency decreased peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and its target gene expression. Additionally, administration of ZLN005, a potent PGC-1α activator, partially protected against high glucose and palmitic acid induced mitochondria dysfunction and lipid accumulation in vitro.
Our study provides compelling evidence supporting the protective role of CH25H in T2DM-induced cardiomyopathy. Furthermore, the regulation of PGC-1α may be intricately involved in this cardioprotective process.
糖尿病心肌病（DCM）是 2 型糖尿病（T2DM）患者死亡的主要原因，但发病机制仍不清楚。本研究旨在探讨胆固醇-25-单加氧酶（CH25H）在 T2DM 诱导的心肌病中的作用。
采用高脂饮食联合链脲佐菌素（HFD/STZ）建立 T2DM 模型。检测 T2DM 模型心脏中的 CH25H 及其产物 25-羟胆固醇（25HC）。给予 AAV9-cTNT-CH25H 或 CH25H 敲除（CH25H）小鼠 HFD/STZ 处理，以实现 CH25H 的功能获得或缺失。通过超声心动图评估心功能，收集心脏组织进行免疫印迹分析、组织学评估和定量聚合酶链反应（qPCR）。使用透射电子显微镜（TEM）和 Seahorse XF Cell Mito Stress Test Kit 评估线粒体形态和功能。进行 RNA 测序分析以确定与 CH25H 缺失相关的分子变化。
T2DM 小鼠心脏中 CH25H 和 25HC 明显降低。HFD/STZ 处理的 CH25H 小鼠表现出线粒体功能和结构受损、脂质堆积增加和心脏功能障碍聚集。相反，接受 AAV9-CH25H 的 T2DM 小鼠表现出心脏保护作用。机制上，RNA 测序和 qPCR 分析显示，CH25H 缺失降低过氧化物酶体增殖物激活受体-γ共激活因子-1α（PGC-1α）及其靶基因的表达。此外，强效 PGC-1α 激活剂 ZLN005 的给药部分保护了体外高葡萄糖和棕榈酸诱导的线粒体功能障碍和脂质堆积。
本研究提供了有力证据支持 CH25H 在 T2DM 诱导的心肌病中的保护作用。此外，PGC-1α 的调节可能与这种心脏保护过程密切相关。
