Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Emergency Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
Int Immunopharmacol. 2023 Nov;124(Pt B):110962. doi: 10.1016/j.intimp.2023.110962. Epub 2023 Sep 28.
Proprotein convertase subtilisin kexin type 9 (PCSK9) was characterized as a protein regulating circulating cholesterol metabolism; however, recent studies demonstrated a role for PCSK9 in inflammatory and autoimmune diseases unrelated to cholesterol alterations. The implication of PCSK9 in myocarditis is unclear and we aim at investigating the roles and mechanisms of PCSK9 in myocarditis. Male BALB/c mice received subcutaneous immunization with MyHC-α peptide on days 0 and 7 to establish the experimental autoimmune myocarditis (EAM) model. PCSK9 inhibitor, evolocumab, was administered subcutaneously once a week starting on day 0 and all mice were euthanized on day 21. Our results showed that PCSK9 inhibition ameliorated the cardiac inflammation of EAM mice. PCSK9 inhibition reduced both the levels of cardiac and peripheral blood PCSK9. We found that CD4 T cells, CD8 T cells, macrophages, and cardiomyocytes in the heart of EAM mice could express PCSK9. PCSK9 inhibition decreased the differentiation of cardiac Th17 cells by lowering ROR-γt levels but had no effects on Th1, Th2, and Treg cell differentiation. In vitro experiments of CD4 T cells, we found that PCSK9 directly promoted Th17 cell differentiation through LDLR/STAT3/ROR-γt pathway. Collectively, we demonstrated that PCSK9 inhibition ameliorated the severity of EAM mice by reducing Th17 cell differentiation. PCSK9 is a promising target for treating myocarditis.
前蛋白转化酶枯草溶菌素 9（PCSK9）最初被认为是一种调节循环胆固醇代谢的蛋白，但最近的研究表明 PCSK9 在与胆固醇变化无关的炎症和自身免疫性疾病中也发挥作用。PCSK9 在心肌炎中的作用尚不清楚，我们旨在研究 PCSK9 在心肌炎中的作用和机制。雄性 BALB/c 小鼠在第 0 天和第 7 天接受 MHC-α 肽的皮下免疫接种，以建立实验性自身免疫性心肌炎（EAM）模型。从第 0 天开始，每周一次皮下给予 PCSK9 抑制剂依洛尤单抗，所有小鼠于第 21 天处死。结果显示，PCSK9 抑制可改善 EAM 小鼠的心脏炎症。PCSK9 抑制降低了心脏和外周血中 PCSK9 的水平。我们发现，EAM 小鼠的 CD4 T 细胞、CD8 T 细胞、巨噬细胞和心肌细胞均可表达 PCSK9。PCSK9 抑制通过降低 ROR-γt 水平减少心脏 Th17 细胞的分化，但对 Th1、Th2 和 Treg 细胞分化没有影响。体外 CD4 T 细胞实验发现，PCSK9 通过 LDLR/STAT3/ROR-γt 通路直接促进 Th17 细胞分化。综上，我们证实 PCSK9 抑制通过减少 Th17 细胞分化改善 EAM 小鼠的严重程度。PCSK9 是治疗心肌炎的一个有希望的靶点。
