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

  • Pharmacol Res. 2024 Nov:209:107460. doi: 10.1016/j.phrs.2024.107460.
Juan Yang  1 ,  Ziyu Li  2 ,  Xinyi Deng  3 ,  Mengru Li  3 ,  Bin Li  4 ,  Rebecca Caroline Thuku  2 ,  Qian Chen  5 ,  Xiang Sun  6 ,  Qiumin Lu  3 ,  Mingqian Fang  7
Affiliations
  • 1. Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, 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, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan, 650201, P. R. 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, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan, 650201, P. R. 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, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan, 650201, P. R. China.
  • 4. Yan'an Hospital of Kunming Medical University, No. 245 Renmin East Road, Kunming, Yunnan 650051, China.
  • 5. Center for Evolution and Conservation Biology, Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou 511458, China.
  • 6. Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
  • 7. 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, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Key Laboratory of Genetic Evolution & Animal Models, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology, the Chinese Academy of Sciences, No.17 Longxin Road, Kunming, Yunnan, 650201, P. R. China. Electronic address: [email protected].
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 4 mg/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.
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