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Atorvastatin ameliorates diabetic cardiomyopathy by enhancing Mzb1-mediated mitigation of oxidative stress and mitochondrial defects.
СтатьяНазвание и аннотация: Перевод в очереди
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Gu Jing, Sun Jiaxi, Wang Xin, Zhang Qi, Liu Yueyang, Xu Qian, Gao Junjia, Li Rong, Zhen Yanru, Zhang Lu, Zhou Ming-Sheng
Аннотация
AIMS: Diabetic cardiomyopathy (DCM) is characterized with mitochondrial dysfunction and oxidative stress. Although atorvastatin is widely used for diabetes patients for cardiovascular prevention. However, its specific therapeutic impact and underlying mechanism remain incompletely understood. This study investigated whether atorvastatin protects against DCM through the RhoA/KLF4/Mzb1 signaling axis.
MATERIALS AND METHODS: We established DCM model using diabetic db/db mice and high glucose-treated cardiomyocytes and administrated atorvastatin in vivo and in vitro. Cardiac function, fibrosis, apoptosis, and mitochondrial parameters were assessed. Mzb1 knockdown, RhoA siRNA silencing, and chromatin immunoprecipitation-qPCR (ChIP-qPCR) were employed to dissect the regulatory mechanism.
KEY FINDINGS: Atorvastatin significantly ameliorated cardiac function and attenuated myocardial fibrosis and oxidative stress and cardiomyocyte apoptosis, and preserved mitochondrial integrity and bioenergetics. These benefits were abolished by silencing Mzb1, establishing Mzb1 as an essential downstream effector. Mechanistically, ChIP-qPCR confirmed direct KLF4 binding to the Mzb1 promoter, and RhoA activity assay revealed that atorvastatin significantly reduced GTP-bound RhoA levels. Genetic knockdown of RhoA upregulated KLF4 and Mzb1, corroborating pharmacological findings that RhoA negatively regulates KLF4.
SIGNIFICANCE: Our results demonstrate that atorvastatin exerts cardioprotection in DCM through the RhoA/KLF4/Mzb1 signaling pathway, wherein atorvastatin inhibits RhoA, relieves KLF4 suppression, leading to transcriptional activation of Mzb1. These findings identify a novel molecular pathway and therapeutic axis for atorvastatin protection of DCM.
MATERIALS AND METHODS: We established DCM model using diabetic db/db mice and high glucose-treated cardiomyocytes and administrated atorvastatin in vivo and in vitro. Cardiac function, fibrosis, apoptosis, and mitochondrial parameters were assessed. Mzb1 knockdown, RhoA siRNA silencing, and chromatin immunoprecipitation-qPCR (ChIP-qPCR) were employed to dissect the regulatory mechanism.
KEY FINDINGS: Atorvastatin significantly ameliorated cardiac function and attenuated myocardial fibrosis and oxidative stress and cardiomyocyte apoptosis, and preserved mitochondrial integrity and bioenergetics. These benefits were abolished by silencing Mzb1, establishing Mzb1 as an essential downstream effector. Mechanistically, ChIP-qPCR confirmed direct KLF4 binding to the Mzb1 promoter, and RhoA activity assay revealed that atorvastatin significantly reduced GTP-bound RhoA levels. Genetic knockdown of RhoA upregulated KLF4 and Mzb1, corroborating pharmacological findings that RhoA negatively regulates KLF4.
SIGNIFICANCE: Our results demonstrate that atorvastatin exerts cardioprotection in DCM through the RhoA/KLF4/Mzb1 signaling pathway, wherein atorvastatin inhibits RhoA, relieves KLF4 suppression, leading to transcriptional activation of Mzb1. These findings identify a novel molecular pathway and therapeutic axis for atorvastatin protection of DCM.