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miR-340-5p Mediates Cardiomyocyte Oxidative Stress in Diabetes-Induced Cardiac Dysfunction by Targeting Mcl-1
Yinghong Zhu1, Xuewen Yang1, Jing Zhou2
1Department of Cardiology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
Abstract:
Diabetic cardiomyopathy (DCM) is initially characterized by early diastolic dysfunction, left ventricular remodeling, hypertrophy, and myocardial fibrosis, and it is eventually characterized by clinical heart failure. MicroRNAs (miRNAs), endogenous small noncoding RNAs, play significant roles in diabetes mellitus (DM). However, it is still largely unknown about the mechanism that links miRNAs and the development of DCM. Here, we aimed to elucidate the mechanism underlying the potential role of microRNA-340-5p in DCM in db/db mouse, which is a commonly used model of type 2 DM and diabetic complications that lead to heart failure. We first demonstrated that miR-340-5p expression was dramatically increased in heart tissues of mice and cardiomyocytes under diabetic conditions. Overexpression of miR-340-5p exacerbated DCM, which was reflected by extensive myocardial fibrosis and more serious dysfunction in db/db mice as represented by increased apoptotic cardiomyocytes, elevated ROS production, and impaired mitochondrial function. Inhibition of miR-340-5p by a tough decoy (TUD) vector was beneficial for preventing ROS production and apoptosis, thus rescuing diabetic cardiomyopathy. We identified myeloid cell leukemia 1 (Mcl-1) as a major target gene for miR-340-5p and showed that the inhibition of Mcl-1 was responsible for increased functional loss of mitochondria, oxidative stress, and cardiomyocyte apoptosis, thereby caused cardiac dysfunction in diabetic mice. In conclusion, our results showed that miR-340-5p plays a crucial role in the development of DCM and can be targeted for therapeutic intervention.
Insights
MicroRNA-340-5p exacerbates diabetic cardiomyopathy (DCM) by targeting Mcl-1, leading to mitochondrial dysfunction and apoptosis. Inhibiting this microRNA may offer a therapeutic strategy for DCM in diabetes mellitus.
Area of Science:
- Cardiovascular Biology
- Molecular Endocrinology
- Genetics and Genomics
Background:
- Diabetic cardiomyopathy (DCM) involves cardiac remodeling and dysfunction, often progressing to heart failure.
- MicroRNAs (miRNAs) are implicated in diabetes mellitus (DM) pathogenesis, but their specific role in DCM development remains unclear.
- Understanding the molecular mechanisms linking miRNAs to DCM is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of microRNA-340-5p (miR-340-5p) in the development of diabetic cardiomyopathy (DCM) using a db/db mouse model.
- To elucidate the underlying molecular mechanisms by which miR-340-5p influences cardiac function in diabetic conditions.
- To identify potential therapeutic targets for DCM based on miR-340-5p activity.
Main Methods:
- Assessed miR-340-5p expression in cardiac tissues and cardiomyocytes of db/db mice under diabetic conditions.
- Utilized overexpression and inhibition (tough decoy vector) of miR-340-5p to evaluate its impact on DCM.
- Investigated downstream effects including myocardial fibrosis, cardiomyocyte apoptosis, reactive oxygen species (ROS) production, and mitochondrial function.
- Identified and validated myeloid cell leukemia 1 (Mcl-1) as a direct target of miR-340-5p.
Main Results:
- miR-340-5p expression was significantly upregulated in the hearts of diabetic mice and cardiomyocytes.
- Overexpression of miR-340-5p worsened DCM, characterized by increased fibrosis, apoptosis, ROS, and impaired mitochondrial function.
- Inhibition of miR-340-5p ameliorated these pathological changes, demonstrating a protective effect against DCM.
- miR-340-5p directly targets Mcl-1, and Mcl-1 inhibition mediates mitochondrial dysfunction, oxidative stress, and apoptosis in diabetic hearts.
Conclusions:
- miR-340-5p plays a critical role in promoting the development and progression of diabetic cardiomyopathy.
- The mechanism involves miR-340-5p-mediated suppression of Mcl-1, leading to mitochondrial damage and cardiomyocyte death.
- Targeting miR-340-5p presents a promising therapeutic avenue for managing diabetic cardiomyopathy.
