Cross-Talk Between PCSK9 and Damaged mtDNA in Vascular Smooth Muscle Cells: Role in Apoptosis

• Published in: Antioxidants & redox signaling Vol. 25; no. 18; p. 997
• Main Authors: Ding, Zufeng, Liu, Shijie, Wang, Xianwei, Mathur, Pankaj, Dai, Yao, Theus, Sue, Deng, Xiaoyan, Fan, Yubo, Mehta, Jawahar L
• Format: Journal Article
• Language: English
• Published: United States 20.12.2016
• Subjects: Animals; Apoptosis - genetics; Autophagy; DNA Damage; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Endodeoxyribonucleases - metabolism; Gene Expression; Humans; Lipopolysaccharides - adverse effects; Mice; Mice, Knockout; Mitochondria - genetics; Mitochondria - metabolism; Models, Biological; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Proprotein Convertase 9 - genetics; Proprotein Convertase 9 - metabolism; Protein Binding; Reactive Oxygen Species - metabolism; TOR Serine-Threonine Kinases; smooth muscle cells; PCSK9; apoptosis; mtDNA damage
• ISSN: 1557-7716
• DOI: 10.1089/ars.2016.6631

The present study was designed to investigate a possible interaction between vascular smooth muscle cell (SMC)-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) and mitochondrial DNA (mtDNA) damage. Treatment of cultured SMCs with the proinflammatory stimulus lipopolysaccharide (LPS) stimulated PCSK9 release and induced mtDNA damage. PCSK9 inhibition by its siRNA reduced, and its enhancement increased, mtDNA damage. Induction of mitochondria-derived reactive oxygen species (mtROS) (by rotenone, thenoyltrifluoroacetone, or antimycin A) enhanced mtDNA damage as well as PCSK9 release, suggesting a role of mtROS in PCSK9-mtDNA damage interplay. Induction of mtDNA damage (with the autophagy inhibitor, 3-methyladenine, or DNase II inhibition) enhanced PCSK9 expression, and inhibition of mtDNA damage (with the autophagy inducer, rapamycin) reduced PCSK9 expression, indicating bidirectional interplay between PCSK9 and mtDNA damage. Other studies showed that p38 MAPK is involved in PCSK9-induced mtDNA damage, and mammalian target of rapamycin activation plays a role in mtDNA damage-induced PCSK9 release. Functional impact of PCSK9-mtDNA damage cross-talk was evident in the form of SMC apoptosis, which was enhanced in cells treated with recombinant human PCSK9, but inhibited in cells treated with PCSK9 siRNA. Last, LPS administration in wild-type mice resulted in simultaneous PCSK9 release and mtDNA damage, but mtDNA damage was minimal in PCSK9-null mice given LPS. Vascular SMC-derived PCSK9 induces mtDNA damage, and damaged mtDNA fragments stimulate PCSK9 release mediated, at least in part, by mtROS. These observations suggest positive feedback interplay between SMC-derived PCSK9 and mtDNA damage in the proinflammatory milieu involving mtROS. This interaction results in cellular injury, characterized by apoptosis-a hallmark of atherosclerosis. Antioxid. Redox Signal. 25, 997-1008.