title: Cross-Talk Between PCSK9 and Damaged mtDNA in Vascular Smooth Muscle Cells: Role in Apoptosis.
abstract: 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.
authors.affiliation: 1 Central Arkansas Veterans Healthcare System, The University of Arkansas for Medical Sciences , Little Rock, Arkansas.|2 Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University , Beijing, China .
authors.forename: Zufeng
authors.initials: Z
authors.lastname: Ding
authors.affiliation: 1 Central Arkansas Veterans Healthcare System, The University of Arkansas for Medical Sciences , Little Rock, Arkansas.
authors.forename: Shijie
authors.initials: S
authors.lastname: Liu
authors.affiliation: 1 Central Arkansas Veterans Healthcare System, The University of Arkansas for Medical Sciences , Little Rock, Arkansas.
authors.forename: Xianwei
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1 Central Arkansas Veterans Healthcare System, The University of Arkansas for Medical Sciences , Little Rock, Arkansas.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Mathur
authors.affiliation: 1 Central Arkansas Veterans Healthcare System, The University of Arkansas for Medical Sciences , Little Rock, Arkansas.
authors.forename: Yao
authors.initials: Y
authors.lastname: Dai
authors.affiliation: 1 Central Arkansas Veterans Healthcare System, The University of Arkansas for Medical Sciences , Little Rock, Arkansas.
authors.forename: Sue
authors.initials: S
authors.lastname: Theus
authors.affiliation: 2 Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University , Beijing, China .
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Deng
authors.affiliation: 2 Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University , Beijing, China .
authors.forename: Yubo
authors.initials: Y
authors.lastname: Fan
authors.affiliation: 1 Central Arkansas Veterans Healthcare System, The University of Arkansas for Medical Sciences , Little Rock, Arkansas.
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008070:Lipopolysaccharides / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D000071449:Proprotein Convertase 9 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II; D000071449:Proprotein Convertase 9
keywords: PCSK9; apoptosis; mtDNA damage; smooth muscle cells