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Anti-hyperlipidemic, Anti-inflammatory, and Ameliorative Effects of DRP1 Inhibition in Rats with Experimentally Induced Myocardial Infarction

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Abstract

This study aims to investigate the biological role of DRP1 in myocardial infarction (MI) in concert with hyperlipidemia (HL). Based on the available literatures, 10 genes related to MI with HL (HL-MI) were screened and detected in clinical samples. High-fat diet (HFD) was used to establish HL rat models, after which the rats were subcutaneously injected with PBS or isoproterenol hydrochloride to induce acute MI. Then, rats with HL-MI were injected with pcDNA3.1, pcDNA3.1-DRP1, sh-NC, or sh-DRP1. Serum levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) were measured. Cardiac function was evaluated by detecting left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF). Infarct size and histopathological changes were assessed as well as myocardial apoptosis and collagen deposition. The concentration of IL-6, IL-1β, and TNF-α in rat serum and cardiac tissues was also measured by ELISA. Mitochondrial function was shown by measuring the morphology, mitochondrial membrane potential (MMP), and intracellular reactive oxygen species (ROS) level. Pro-apoptotic proteins (Bax, caspase-1, and cleaved caspase-1) and NLRP3 inflammasome activation were also assessed. The expressions of the 10 genes were measured in clinical samples and DRP1 was selected for further experiments with significantly upregulated expression in MI patients. HFD-induced rats showed increased body weight, concurrent with higher levels of TG, TC, and LDL-C and lower HDL-C level. Compared with the BD-PBS group, the HFD-PBS group presented higher mRNA and protein expression levels of DRP1, exacerbated cardiac functions, enlarged infarct size, loss of cardiomyocytes, and disordered island cardiomyocytes. In the HL-MI rat model, injection of pcDNA3.1-DRP1 enhanced the levels of serum lipids and inflammation cytokines, induced loss of a number of cardiomyocytes and collagen deposition, and decreased LVFS and LVEF, while injection of sh-DRP1 ameliorated myocardial injuries, inflammation, and cardiomyocyte apoptosis and fibrosis. In coronary artery endothelial cells from the rats, loss of MMP was observed in the HFD-MI, LV-NC, LV-DRP1, and sh-NC groups and concomitantly, the sh-DRP1group showed increased MMP and decreased levels of mitochondrial ROS, cytochrome C, pro-apoptotic proteins, and NLRP3. Inhibition of DRP1 markedly suppressed HL, systematic inflammation, and myocardial injuries induced by HL-MI through partly restoring mitochondrial function and reducing NLRP3 expression.

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Data Availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Thanks for the support of Shenzhen Science and Technology Research Funding (Grant No. 20170502165510880).

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Author notes

  1. Xiehui Chen and Jinjie Liang have contributed equally to this research.

Authors and Affiliations

  1. Shenzhen Longhua District Central Hospital (The Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University), Shenzhen, 518110, Guangdong, People’s Republic of China

    Xiehui Chen

  2. Department of Geriatrics Cardiovascular Medicine, Fuwai Hospital Chinese Academy of Medical Sciences, No. 12, Langshan Road, Nanshan District, Shenzhen, 518112, Guangdong, People’s Republic of China

    Jinjie Liang & Wugang Bin

  3. Shenzhen RealOmics (Biotech) Co., Ltd., Shenzhen, 518081, Guangdong, People’s Republic of China

    Hongmin Luo & Xu Yang

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  1. Xiehui Chen
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Correspondence to Xiehui Chen.

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The authors declare that there is no conflict of interest regarding the publication of this paper.

Ethical Statement

This study was carried out with the approval of the ethical committee of Fuwai Hospital Chinese Academy of Medical Sciences and informed consent form was acquired from each patient. All participants had been informed about the aim and requirements of this study before being enrolled. Animal experiments conformed to the Guide for the Care and Use of Laboratory Animals and relative regulations.

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Chen, X., Liang, J., Bin, W. et al. Anti-hyperlipidemic, Anti-inflammatory, and Ameliorative Effects of DRP1 Inhibition in Rats with Experimentally Induced Myocardial Infarction. Cardiovasc Toxicol 21, 1000–1011 (2021). https://doi.org/10.1007/s12012-021-09691-w

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  • DOI: https://doi.org/10.1007/s12012-021-09691-w

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