Kallikrein inhibitor derived from immunoglobulin heavy chain junction region possesses anti-thromboinflammation potential

Juan Yang; Ziyu Li; Xinyi Deng; Mengru Li; Bin Li; Rebecca Caroline Thuku; Qian Chen; Xiang Sun; Qiumin Lu; Mingqian Fang

doi:10.1016/j.phrs.2024.107460

Kallikrein inhibitor derived from immunoglobulin heavy chain junction region possesses anti-thromboinflammation potential

Pharmacol Res. 2024 Oct 9:107460. doi: 10.1016/j.phrs.2024.107460. Online ahead of print.

Authors

Juan Yang¹, Ziyu Li², Xinyi Deng³, Mengru Li⁴, Bin Li⁵, Rebecca Caroline Thuku², Qian Chen⁶, Xiang Sun⁷, Qiumin Lu³, Mingqian Fang⁸

Affiliations

¹ Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China; Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Sino-African Joint Research Center, and Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan, 650201, PR China.
² Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Sino-African Joint Research Center, and Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan, 650201, PR China; Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China.
³ Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Sino-African Joint Research Center, and Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan, 650201, PR China.
⁴ Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Sino-African Joint Research Center, and Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan, 650201, PR China; School of Life Sciences, Anhui University, Hefei 230601, China.
⁵ Yan'an Hospital of Kunming Medical University. No. 245 Renmin East Road, Kunming, Yunnan 650051, China.
⁶ Center for Evolution and Conservation Biology, Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China.
⁷ Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China.
⁸ Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Sino-African Joint Research Center, and Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan, 650201, PR China. Electronic address: fangmingqian@mail.kiz.ac.cn.

PMID: 39393436
DOI: 10.1016/j.phrs.2024.107460

Abstract

Influenza vaccination is associated with a reduced incidence of cardiovascular events, cardiovascular death, and all-cause mortality. However, the functional role of the associated immunoglobulin remains unclear. This study identified a specific influenza-related immunoglobulin heavy chain junction region sequence (Ser-Leu-Gly-Ala-Ser-Asp, SD6) that inhibited plasma kallikrein (PKa) activity to resist thromboinflammatory responses and stroke injury. PKa is considered an attractive therapeutic target for alleviating the complications of thrombophilia-induced inflammation. In vitro, SD6 prolonged plasma recalcification and activated partial thromboplastin time, with no effects on bleeding risk-related prothrombin time, indicating selective inhibition of the intrinsic coagulation pathway. Correspondingly, at doses ranging from 0.25 to 4mg/kg, SD6 attenuated arterial and cortical venous thrombosis in FeCl₃-induced and photochemically induced mice, without impacting hemorrhage risk, and further mitigated cerebral inflammatory injury in a mouse model of transient middle cerebral artery occlusion ischemic stroke. These findings suggest that SD6 may serve as a potential therapeutic agent for the treatment of thromboinflammatory conditions.

Keywords: anti-thromboinflammation; immunoglobulin heavy chain junction region; kallikrein; peptide.