Contrasting Effects of Endogenous and extracellular PCSK9 on Inflammation, Lipid alteration and Cell death.

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the major regulators of low-density lipoprotein receptor (LDLR). While information on role and regulation of PCSK9 in lung is very limited, recent discovery of PCSK9 in A549 highlights a potential function of PCSK9 in lung. Our study focuses on understanding the role and regulation of PCSK9 in the lung. Experiments involved measurement of PCSK9 in bronchioalveolar lavage fluid (BALF), single cell sequencing analysis, and exposure of lung epithelial cells to PCSK9, cigarette smoke extract (CSE), and staurosporine. Inhibition of endogenous PCSK9 expression was followed by bulk RNA sequencing. PCSK9 levels were higher in BALF of smokers with or without chronic obstructive pulmonary diseases (COPD) compared to BALF of nonsmokers. PCSK9-stimulated cells induced proinflammatory cytokines and activation of MAPKp38. PCSK9 transcripts were highly expressed in healthy individuals compared to COPD, pulmonary fibrosis or pulmonary systemic sclerosis. CSE reduced PCSK9 levels in undifferentiated PBEC but induced in differentiated PBEC. PCSK9 inhibition affected biological pathways, inducing lipid peroxidation, and higher level of apoptosis in response to staurosporine. Our results suggest that higher levels of PCSK9 in BALF acts as an inflammatory marker. Furthermore, extracellular and endogenous PCSK9 play different roles.