Priyanka Arya - Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi - ۱۱۰۰۶۲, India
Uma Bhandari - Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi - ۱۱۰۰۶۲, India
Kalicharan Sharma - Department of Pharmaceutical Chemistry, SPS, DPSRU, New Delhi-۱۱۰۰۱۷
Priyanka Bansal - Department of Pharmacology, School of Pharmaceutical Education & Research (SPER), Jamia Hamdard, New Delhi - ۱۱۰۰۶۲, India

Objective(s): Excess intake of a high-fatty diet (HFD) together with zymosan administration mediates vasculitis response which leads to impaired serum lipid levels and causes arterial stiffness. In the development of new cholesterol-lowering medications, PCSK۹ inhibitor (proprotein convertase subtilisin/kexin type ۹) is an emerging therapeutic. The goal of the present study was to see whether anti-PCSK۹ mAb۱ might prevent vasculitis in C۵۷BL/۶ mice by blocking TLR۲/NF-B activation in HFD and Zymosan-induced vasculitis. Materials and Methods: Protein-protein molecular docking was performed to validate the binding affinity of anti-PCSK۹ mAb۱ against TLR۲. Under the experimental study, mice were randomly allocated to the following groups: Group I: standard mice diet (۳۰ days) + Zymosan vehicle (sterile PBS solution of ۵mg/ml on ۸th day); Group II: HFD (۳۰ days) + Zymosan ( single IP dose ۸۰ mg/kg on day ۸th); Group III: HFD+Zymosan + anti-PCSK۹ mAb۱ (۶ mg/kg, s.c. on ۱۰th and ۲۰th days); Group IV: HFD+Zymosan+anti-PCSK۹ mAb۱ (۱۰ mg/kg, s.c. on ۱۰th and ۲۰th days).Results: In comparison with the low dose of anti-PCSK۹ mAb۱ (۶ mg/kg), the high dose of anti-PCSK۹ mAb۱ (۱۰ mg/kg) together with HFD and Zymosan inhibited vasculitis more effectively by decreasing aortic TLR۲ and NF-B levels, reducing serum TNF- and IL-۶, and up-regulating liver LDLR levels, which down-regulated serum LDL-C and improved serum lipids levels. Histopathological studies showed that anti-PCSK۹ mAb۱ treatment reduced plaque accumulation in the aorta of mice.Conclusion: These findings indicate that anti-PCSK۹ mAb۱ has therapeutic potential in reducing HFD and Zymosan-induced vascular inflammation.  

Anti-PCSK۹ antibody, High-fat diet, Inflammation, Toll-Like Receptor, Zymosan