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Bicyclol Alleviates Streptozotocin-induced Diabetic Cardiomyopathy By Inhibiting Chronic Inflammation And Oxidative Stress

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Abstract

Purpose

Diabetic cardiomyopathy (DCM) is a common and severe complication of diabetes. Inflammation and oxidative stress play important roles in DCM development. Bicyclol is a hepatoprotective drug in China that exerts anti-inflammatory effects by inhibiting the MAPK and NF-κB pathways to prevent obesity-induced cardiomyopathy. Our purpose was to explore the effect and mechanism of bicyclol on DCM.

Methods

A type 1 diabetes mouse model was established using C57BL/6 mice by intraperitoneal injection of STZ. The therapeutic effect of bicyclol was evaluated in both heart tissues of diabetic mice and high concentration of glucose (HG)-stimulated H9c2 cells.

Results

We showed that bicyclol significantly attenuated diabetes-induced cardiac hypertrophy and fibrosis, which is accompanied by the preservation of cardiac function in mice. In addition, bicyclol exhibited anti-inflammatory and anti-oxidative effects both in vitro and in vivo. Furthermore, bicyclol inhibited the hyperglycemia-induced activation of MAPKs and NF-κB pathways, while upregulating the Nrf-2/HO-1 pathway to exhibit protective effects.

Conclusion

Our data indicate that bicyclol could be a promising cardioprotective agent in the treatment of DCM.

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Data Availability

All the data in this study are available upon reasonable request from the corresponding author.

Code Availability

Not applicable.

Abbreviations

BIC:

bicyclol

BNP:

brain natriuretic peptide

BSA:

bovine serum albumin

CK-MB:

creatine kinase-MB

CMC-Na:

Carboxymethylcellulose sodium

Col-1:

type 1 collagen

DAB:

diaminobenzidine

DCM:

diabetic cardiomyopathy

DM:

diabetes mellitus

DMSO:

dimethylsulphoxide

DMEM:

Dulbecco’s Modified Eagle’s Medium

EF:

ejection fraction

ERK:

extracellular regulated protein kinases

FBS:

fetal bovine serum

FS:

fractional shortening

HG:

high concentration glucose

HO-1:

heme oxygenase-1

IL-1β:

interleukin 1β

IL-6:

interleukin 6

IκB-α:

inhibitor of NF-κB-α

JNK:

c-Jun N-terminal kinase

Keap-1:

Kelch-like ECH-associated protein 1

LDH:

lactic dehydrogenase

MAPK:

mitogen-activated protein kinase

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazoliumbromide

NAFLD:

nonalcoholic fatty liver

NF-κB:

nuclear factor kappa-B

Nrf-2:

nuclear factor-erythroid 2-related factor 2

ROS:

reactive oxygen species

STZ:

streptozotocin

T1DM:

type 1 diabetes mellitus

TGF-β:

transforming growth factor-β

TNF-α:

tumor necrosis factor-α

β-Myhc:

β-myosin heavy chain

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Funding

This study was supported by the National Natural Science Foundation of China (82170373 to Y.W.).

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Authors and Affiliations

  1. Department of Pharmacy, The Affiliated Xiangshan Hospital of Wenzhou Medical University, Zhejiang, 315700, Ningbo, China

    Lingxi Zhang, Xuedan Wu, Li Zheng, Xuelian Xu, Yongsheng Jiang, Yi Wang & Ying He

  2. Chemical Biology Research Center, School of Pharmacological Sciences, Wenzhou Medical University, Zhejiang, 325035, Wenzhou, China

    Lingxi Zhang, Chenghong Hu, Bo Jin, Bin Bai, Jing Liao, Leiming Jin, Minxiu Wang, Weiwei Zhu & Yi Wang

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  1. Lingxi Zhang
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Contributions

Yi Wang and Ying He contributed to the literature search and study design. Lingxi Zhang, Chenghong Hu, Bo Jin, Jing Liao, Bin Bai, Leiming Jin, Minxiu Wang, Weiwei Zhu, Xuelian Xu and Li Zheng carried out experiments. Lingxi Zhang, Xuedan Wu and Yongsheng Jiang contributed to data collection and analysis. Lingxi Zhang participated in the drafting of the article. Yi Wang and Ying He revised the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Yi Wang or Ying He.

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Ethics Statement

All animal experiments were in compliance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Welfare Committee of Wenzhou Medical University (Approved ID: wydw2018-0124).

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Zhang, L., Hu, C., Jin, B. et al. Bicyclol Alleviates Streptozotocin-induced Diabetic Cardiomyopathy By Inhibiting Chronic Inflammation And Oxidative Stress. Cardiovasc Drugs Ther 38, 555–568 (2024). https://doi.org/10.1007/s10557-023-07426-3

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