Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
J Adv Res. 2024 Jul;61:211-221. doi: 10.1016/j.jare.2023.09.007. Epub 2023 Sep 12.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is implicated in the pathogenesis and progression of autoimmune disease. Patients with rheumatoid arthritis (RA) are at high risk of developing atrial fibrillation (AF), while whether PCSK9 is involved in the onset of AF among RA patients remains unclear.
To explore the role of PCSK9 in the occurrence of AF in RA patients and decipher the underlying mechanism.
We established a rat model of collagen-induced arthritis (CIA) by immunization with type II collagen in Freund's incomplete adjuvant. Atrial electrophysiological test was used to evaluate AF susceptibility. We performed a clinical study to examine the correlation between PCSK9 level and AF, which recruited healthy control, RA patients and RA patients complicated with AF. Evolocumab (a monoclonal antibody of PCSK9) is administered via intraperitoneal injection in CIA rats to assess the role of PCSK9 in RA-related AF. LPS-RS (LPS inhibitor), clodronate liposomes (depletion of macrophages), and cell co-culture model were used to dissect the mechanism underlying PCSK9 promotes AF.
AF inducibility and duration were higher in CIA rats, accompanied by elevated plasma and atrial PCSK9. Interestingly, compared with healthy control subjects, patients with RA showed an increase in PCSK9, and the PCSK9 is much higher in RA patients complicated with AF. The level of PCSK9 was independently associated with AF risk in RA patients. In the in vivo experiment, evolocumab reduced AF susceptibility, and ameliorated atrial structural remodeling of CIA rats. Mechanistically, augmented LPS in CIA rats led to an increase in PCSK9, which exacerbated fibrosis of cardiac fibroblasts and apoptosis of cardiac myocytes by enhancement of M1 macrophages polarization and inflammation, thereby contributing to AF.
This study suggests that elevated PCSK9 causes atrial structural remodeling by enhancement of M1 macrophages polarization in atria, and evolocumab can effectively protects CIA rats from AF.
前蛋白转化酶枯草溶菌素 9（PCSK9）与自身免疫性疾病的发病机制和进展有关。类风湿关节炎（RA）患者发生心房颤动（AF）的风险较高，而 PCSK9 是否参与 RA 患者 AF 的发生尚不清楚。
探讨 PCSK9 在 RA 患者 AF 发生中的作用，并阐明其潜在机制。
我们通过在不完全弗氏佐剂中免疫 II 型胶原建立胶原诱导性关节炎（CIA）大鼠模型。心房电生理测试用于评估 AF 易感性。我们进行了一项临床研究，以检查 PCSK9 水平与 AF 的相关性，该研究招募了健康对照、RA 患者和 RA 患者合并 AF。CIA 大鼠通过腹腔注射给予依洛尤单抗（PCSK9 的单克隆抗体），以评估 PCSK9 在 RA 相关 AF 中的作用。LPS-RS（LPS 抑制剂）、氯膦酸脂质体（巨噬细胞耗竭）和细胞共培养模型用于剖析 PCSK9 促进 AF 的机制。
CIA 大鼠的 AF 易感性和持续时间较高，同时伴有血浆和心房 PCSK9 升高。有趣的是，与健康对照组相比，RA 患者的 PCSK9 升高，而合并 AF 的 RA 患者的 PCSK9 升高更为明显。PCSK9 水平与 RA 患者的 AF 风险独立相关。在体内实验中，依洛尤单抗降低了 AF 易感性，并改善了 CIA 大鼠的心房结构重塑。机制上，CIA 大鼠中升高的 LPS 导致 PCSK9 增加，通过增强 M1 巨噬细胞极化和炎症，加剧心脏成纤维细胞纤维化和心肌细胞凋亡，从而导致 AF。
本研究表明，升高的 PCSK9 通过增强心房中 M1 巨噬细胞极化导致心房结构重塑，依洛尤单抗可有效保护 CIA 大鼠免受 AF 影响。
