Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China; Departments of Biochemistry & Molecular Biology and Physiology & Pharmacology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, Calgary, Alberta, Canada.
Departments of Biochemistry & Molecular Biology and Physiology & Pharmacology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, The University of Calgary, Calgary, Alberta, Canada; Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerosis of Hunan Province, Hengyang Medical College, University of South China, Hengyang City, Hunan Province, 421001, China.
Arch Biochem Biophys. 2021 Jun 15;704:108717. doi: 10.1016/j.abb.2020.108717. Epub 2020 Dec 9.
PCSK9 plays a critical role in cholesterol metabolism via the PCSK9-LDLR axis. Liver-derived, circulating PCSK9 has become a novel drug target in lipid-lowering therapy. Accumulative evidence supports the possible association between PCSK9 and cardiac diseases and their risk factors. PCSK9 exerts various effects in the heart independently of LDL-cholesterol regulation. Acute myocardial infarction (AMI) induces local and systemic inflammation and reactive oxygen species generation, resulting in increased PCSK9 expression in hepatocytes and cardiomyocytes. PCSK9 upregulation promotes excessive autophagy and apoptosis in cardiomyocytes, thereby contributing to cardiac insufficiency. PCSK9 might also participate in the pathophysiology of heart failure by regulating fatty acid metabolism and cardiomyocyte contractility. It also promotes platelet activation and coagulation in patients with atrial fibrillation. PCSK9 is an independent predictor of aortic valve calcification and accelerates calcific aortic valve disease by regulating lipoprotein(a) catabolism. Accordingly, the use of PCSK9 inhibitors significantly reduced infarct sizes and arrhythmia and improves cardiac contractile function in a rat model of AMI. Circulating PCSK9 levels are positively correlated with age, diabetes mellitus, obesity, and hypertension. Here, we reviewed recent clinical and experimental studies exploring the association between PCSK9, cardiac diseases, and their related risk factors and aiming to identify possible underlying mechanisms.
PCSK9 在胆固醇代谢中通过 PCSK9-LDLR 轴发挥关键作用。肝脏来源的循环 PCSK9 已成为降脂治疗的新药物靶点。越来越多的证据支持 PCSK9 与心脏疾病及其危险因素之间可能存在关联。PCSK9 通过独立于 LDL 胆固醇调节的方式在心脏中发挥多种作用。急性心肌梗死（AMI）诱导局部和全身炎症以及活性氧生成，导致肝细胞和心肌细胞中 PCSK9 表达增加。PCSK9 的上调促进心肌细胞中过度的自噬和凋亡，从而导致心脏功能不全。PCSK9 还可能通过调节脂肪酸代谢和心肌细胞收缩性参与心力衰竭的病理生理学。它还促进心房颤动患者的血小板激活和凝血。PCSK9 是主动脉瓣钙化的独立预测因子，并通过调节脂蛋白（a）代谢来加速钙化性主动脉瓣疾病。因此，PCSK9 抑制剂的使用可显著减少 AMI 大鼠模型中的梗塞面积和心律失常，并改善心脏收缩功能。循环 PCSK9 水平与年龄、糖尿病、肥胖和高血压呈正相关。在这里，我们回顾了最近的临床和实验研究，探讨了 PCSK9、心脏疾病及其相关危险因素之间的关系，并旨在确定可能的潜在机制。
