Adverse left ventricular remodeling by glycoprotein nonmetastatic melanoma protein B in myocardial infarction.
Cardiac diseases are the leading cause of death. Available treatment approaches are not sufficient to reverse persistent cardiac damage after injury; thus, the search for new therapeutic targets is essential. Our microarray-based screening in rat hearts 24 h after myocardial infarction (MI) yielded glycoprotein nonmetastatic melanoma protein B (GPNMB), which is known to be involved in inflammation and fibrosis after tissue injury. However, its role in the heart was elusive. We found increased cardiac expression levels of GPNMB in rats and mice after MI. Analysis of DBA/2J mice, which lack functional GPNMB due to a spontaneous point mutation, showed that systemic GPNMB deficiency was associated with preserved cardiac function and less left ventricular dilation after MI compared with DBA/2J mice with reconstituted GPNMB expression. These improvements were associated with decreased expression of matrix metalloproteinase 9, the cardiac stress genes for natriuretic peptides (atrial natriuretic peptide and brain natriuretic peptide), and β-myosin heavy chain after MI. Moreover, GPNMB deficiency attenuated the dilated cardiomyopathy in muscle lim protein knockout mice but could not prevent cardiac hypertrophy induced by isoprenaline infusion. This is the first experimental study to show that GPNMB adversely influences myocardial remodeling.-Järve, A., Mühlstedt, S., Qadri, F., Nickl, B., Schulz, H., Hübner, N., Özcelik, C., Bader, M. Adverse left ventricular remodeling by glycoprotein nonmetastatic melanoma protein B in myocardial infarction.
Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Berlin-Brandenburg School of Regenerative Therapies, Berlin, Germany.
Anne
A
Järve
Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Faculty of Mathematics and Natural Sciences I, Humboldt-University Berlin, Germany.|Berlin Institute of Health, Berlin, Germany.
Silke
S
Mühlstedt
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Fatimunnisa
F
Qadri
Max Delbrück Center for Molecular Medicine, Berlin, Germany.|Berlin Institute of Health, Berlin, Germany.
Bernadette
B
Nickl
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Herbert
H
Schulz
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Norbert
N
Hübner
Charité-University Medicine, Berlin, Germany.
Cemil
C
Özcelik
Max Delbrück Center for Molecular Medicine, Berlin, Germany; mbader@mdc-berlin.de.|Berlin Institute of Health, Berlin, Germany.|Charité-University Medicine, Berlin, Germany.|German Center for Cardiovascular Research (DZHK), Berlin, Germany; and.|Institute for Biology, University of Lübeck, Lübeck, Germany.
Michael
M
Bader
D000818:Animals; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism*; D017354:Point Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013234:Stem Cells / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
D005136:Eye Proteins; C445671:Gpnmb protein, mouse; C503043:Gpnmb protein, rat; D060588:LIM Domain Proteins; D008562:Membrane Glycoproteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C090114:cysteine and glycine-rich protein 3
DBA/2J; heart; inflammation; macrophages; osteoactivin