Anti-infection effects of heparin on SARS-CoV-2 in a diabetic mouse model

Zhongyun Zhang; Ning Zhang; Xuancheng Lu; Min Zhou; Xiaoxiang Yan; Weiqiong Gu; Jingru Yang; Qin Zhang; Cheng Zhang; Yuhuan Gong; Mingjun Jia; Xiaoyu Zhang; Peng Ning; Mei Liu; Xiaoyan Li; Xiaomeng Shi; Wenjun Liu; George F. Gao; Guang Ning; Jiqiu Wang; Yuhai Bi

doi:10.24272/j.issn.2095-8137.2023.108

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Zhongyun Zhang, Ning Zhang, Xuancheng Lu, Min Zhou, Xiaoxiang Yan, Weiqiong Gu, Jingru Yang, Qin Zhang, Cheng Zhang, Yuhuan Gong, Mingjun Jia, Xiaoyu Zhang, Peng Ning, Mei Liu, Xiaoyan Li, Xiaomeng Shi, Wenjun Liu, George F. Gao, Guang Ning, Jiqiu Wang, Yuhai Bi. Anti-infection effects of heparin on SARS-CoV-2 in a diabetic mouse model. Zoological Research, 2023, 44(6): 1003-1014. doi: 10.24272/j.issn.2095-8137.2023.108

Citation:

Zhongyun Zhang, Ning Zhang, Xuancheng Lu, Min Zhou, Xiaoxiang Yan, Weiqiong Gu, Jingru Yang, Qin Zhang, Cheng Zhang, Yuhuan Gong, Mingjun Jia, Xiaoyu Zhang, Peng Ning, Mei Liu, Xiaoyan Li, Xiaomeng Shi, Wenjun Liu, George F. Gao, Guang Ning, Jiqiu Wang, Yuhai Bi. Anti-infection effects of heparin on SARS-CoV-2 in a diabetic mouse model. Zoological Research, 2023, 44(6): 1003-1014. doi: 10.24272/j.issn.2095-8137.2023.108

Citation:

Zhongyun Zhang, Ning Zhang, Xuancheng Lu, Min Zhou, Xiaoxiang Yan, Weiqiong Gu, Jingru Yang, Qin Zhang, Cheng Zhang, Yuhuan Gong, Mingjun Jia, Xiaoyu Zhang, Peng Ning, Mei Liu, Xiaoyan Li, Xiaomeng Shi, Wenjun Liu, George F. Gao, Guang Ning, Jiqiu Wang, Yuhai Bi. Anti-infection effects of heparin on SARS-CoV-2 in a diabetic mouse model. Zoological Research, 2023, 44(6): 1003-1014. doi: 10.24272/j.issn.2095-8137.2023.108

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Anti-infection effects of heparin on SARS-CoV-2 in a diabetic mouse model

doi: 10.24272/j.issn.2095-8137.2023.108

Zhongyun Zhang^{1, 2, #},
Ning Zhang^{3, #},
Xuancheng Lu^{4, #},
Min Zhou⁵,
Xiaoxiang Yan⁶,
Weiqiong Gu^{1, 2},
Jingru Yang⁷,
Qin Zhang⁴,
Cheng Zhang³,
Yuhuan Gong³,
Mingjun Jia³,
Xiaoyu Zhang³,
Peng Ning³,
Mei Liu⁴,
Xiaoyan Li⁴,
Xiaomeng Shi⁴,
Wenjun Liu^{3, 8},
George F. Gao^{3, 4, 8},
Guang Ning^{1, 2},
Jiqiu Wang^{1, 2
,
,},
Yuhai Bi^{3, 7, 8
,
,}

1.
Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai 200025, China
3.
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing 100101, China
4.
Laboratory Animal Center, Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China
5.
Department of Respiratory and Critical Care Medicine, Institute of Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
6.
Department of Cardiology, Institute of Cardiovascular Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
7.
School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
8.
University of Chinese Academy of Sciences, Beijing 100049, China

Supplementary data to this article can be found online.
The authors declare that they have no competing interests.
Y.B., J.W. conceived the concept; Y.B., J.W., and N.Z. designed the study and analyzed the data; N.Z., Z.Z., J.Y., C.Z., Y.G., M.J., N.P., and X.Z. performed the experiments; X.Y. provided clinical data; M.Z., W.G., and G.N. assisted in data analysis; Z.Z. analyzed the clinical data; J.W. and Z.Z. constructed the mouse models; X.L., Q.Z., M.L., X.L., and X.S. assisted with H&E staining; Y.B., N.Z., and Z.Z. wrote the manuscript; Y.B., J.W., X.L., N.Z., Z.Z., G.N., and G.G. revised the manuscript. All authors read and approved the final version of the manuscript.
#Authors contributed equally to this work

Funds: This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) (XDB29010102); National Natural Science Foundation of China (NSFC) (91957124, 82161148010, 32041010); Self-supporting Program of Guangzhou Laboratory (SRPG22-001); National Science and Technology Infrastructure of China (National Pathogen Resource Center-NPRC-32); and Management Strategy of the Tertiary Prevention and Treatment of Diabetes Based on DIP system (supported by China Health Promotion Foundation). Y.B. was supported by the Youth Innovation Promotion Association of CAS (Y2021034) and Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202208)

More Information

Corresponding author: E-mail: beeyh@im.ac.cn; wangjq@shsmu.edu.cn
Received Date: 2023-07-02
Accepted Date: 2023-07-24

Published Online: 2023-09-05

Abstract

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in more severe syndromes and poorer outcomes in patients with diabetes and obesity. However, the precise mechanisms responsible for the combined impact of corona virus disease 2019 (COVID-19) and diabetes have not yet been elucidated, and effective treatment options for SARS-CoV-2-infected diabetic patients remain limited. To investigate the disease pathogenesis, K18-hACE2 transgenic (hACE2^Tg) mice with a leptin receptor deficiency (hACE2-Lepr^-/- mice) or high-fat diet background (hACE2-HFD mice) were generated. The two mouse models were intranasally infected with a 5×10⁵ median tissue culture infectious dose (TCID₅₀) of SARS-CoV-2, with serum and lung tissue samples collected at 3 days post-infection. The hACE2-Lepr^-/- mice were then administered a combination of low-molecular-weight heparin (LMWH) (1 mg/kg or 5 mg/kg) and insulin via subcutaneous injection prior to intranasal infection with 1×10⁴ TCID₅₀ of SARS-CoV-2. Daily drug administration continued until the euthanasia of the mice. Analyses of viral RNA loads, histopathological changes in lung tissue, and inflammation factors were conducted. Results demonstrated similar SARS-CoV-2 susceptibility in hACE2^Tg mice under both lean (chow diet) and obese (HFD) conditions. However, compared to the hACE2-Lepr^+/+ mice, hACE2-Lepr^-/- mice exhibited more severe lung injury, enhanced expression of inflammatory cytokines and hypoxia-inducible factor-1α, and increased apoptosis. Moreover, combined LMWH and insulin treatment effectively reduced disease progression and severity, attenuated lung pathological changes, and mitigated inflammatory responses. In conclusion, pre-existing diabetes can lead to more severe lung damage upon SARS-CoV-2 infection, and LMWH may be a valuable therapeutic approach for managing COVID-19 patients with diabetes.
- SARS-CoV-2,
- Diabetes,
- Mouse model,
- Heparin,
- Antiviral therapy

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References(66)

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