Upregulated PCSK9 Level Contributes to Human Pulmonary Microvascular Endothelial Cell Apoptosis in Cigarette Smoke Extract-Induced COPD Models Through TLR4/NF-kappaB Pathway Activation.

Abstract

Chronic obstructive pulmonary disease (COPD) is persistent and can result in irreversible alveolar collapse and increase the risk of cardiovascular disease. PCSK9 belongs to the pro-protein convertase family and is capable of modulating cholesterol metabolism and low-density lipoprotein (LDL). PCSK9 is associated with endothelial dysfunction and its suppression is conducive to vascular function. The aim of this study was to explore PCSK9 expression in the lung tissues of patients with COPD and investigate the regulation of PCSK9 in cigarette smoke extract (CSE)-exposed human pulmonary microvascular endothelial cells (HPMECs) and an in vivo cigarette smoke (CS)-exposed mouse model. PCSK9 is drastically upregulated in the lung tissues of patients with COPD relative to those of individuals who have never smoked. PCSK9 expression in HPMECs and the CS-exposed mouse model was found to increase. Functional assays demonstrated that PCSK9 silencing decreased CS-induced lung injury and neutrophil and macrophage infiltration. PCSK9 silencing also abolished CSE-induced apoptosis by upregulating Bcl-2 and downregulating Bax expression in COPD mice and cell models. PCSK9 silencing alleviated the inflammatory response in the BALF of CS-exposed mice and CSE-treated HPMECs. The protein expression of P65, NLRP3, ASC, TLR4, p-P65, MyD88, and caspase-1 in mouse BALF and HPMECs was inhibited after PCSK9 knockdown. Collectively, these observations indicate the important role of PCSK9 in COPD progression and present promising treatment targets for COPD.