Implication of CD38 gene in autophagic degradation of collagen I in mouse coronary arterial myocytes.
Collagen deposition is a hallmark of atherosclerosis. Although compromised collagen I degradation has been implied in the pathogenesis of atherosclerosis, the molecular mechanisms are still unclear. Thus, we determined the role of CD38, an enzyme involved in cellular calcium modulation and autophagic flux, in the regulation of collagen I degradation in coronary arterial myocytes (CAMs).In primary cultured CAMs from CD38-/-mice, collagen I protein accumulation but not mRNA abundance was significantly increased compared with cells from CD38+/+mice either under control or upon TGF-Beta stimulation. Pharmacological inhibition of the formation of autophagosomes with 3-methyladenine or of autophagolysosomes with a lysosomal functional blocker, bafilomycin A1, induced a similar increase in collagen protein levels, while inhibition of the proteasome by MG132 had no effects on collagen I accumulation. In addition, CD38-deficiency did not change the protein expression of matrix metalloprotein-9 (MMP-9) or tissue inhibitor of metalloproteinase-1 (TIMP-1) in CAMs. Confocal microscopy showed that collagen I deposition was mainly lied within lysosomes or autophagosomes in CD38-/-or TGF-Beta treated CAMs. Collagen I deposition increased when CAMs lack CD38 expression or if autophagy was blocked, which is associated with impaired autophagic degradation of collagen I. This CD38 regulation of autophagic flux may represent a novel mechanism for extracellular matrix (ECM) plasticity of coronary arteries upon atherogenic stimulation.
Department of Aerospace Hygiene, Fourth Military Medical University, Xi'an 710032, People's Republic of China.
Jun-Xiang
JX
Bao
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298.
Qin-Fang
QF
Zhang
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298.
Mi
M
Wang
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298.
Min
M
Xia
Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA and Department of Nephrology, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.
Krishna M
KM
Boini
Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
Erich
E
Gulbins
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298.
Yang
Y
Zhang
Department of Pharmacology & Toxicology, Virginia Commonwealth University, 1220 East Broad Street, P.O.Box 980613, Richmond, VA 23298-0613, pin-lan.li@vcuhealth.org.
Pin-Lan
PL
Li
D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism*; D066273:Diet, Western / Q000009:adverse effects; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D024042:Collagen Type I; D008562:Membrane Glycoproteins; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse