Järve Anne, Mühlstedt Silke, Qadri Fatimunnisa, Nickl Bernadette, Schulz Herbert, Hübner Norbert, Özcelik Cemil, Bader Michael
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Berlin-Brandenburg School of Regenerative Therapies, Berlin, Germany.
FASEB J. 2017 Feb;31(2):556-568. doi: 10.1096/fj.201600613R. Epub 2016 Oct 25.
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.
心脏疾病是主要的死亡原因。现有的治疗方法不足以逆转损伤后持续的心脏损害；因此，寻找新的治疗靶点至关重要。我们在大鼠心肌梗死（MI）后24小时进行的基于微阵列的筛选发现了糖蛋白非转移性黑色素瘤蛋白B（GPNMB），已知其参与组织损伤后的炎症和纤维化过程。然而，它在心脏中的作用尚不清楚。我们发现MI后大鼠和小鼠心脏中GPNMB的表达水平升高。对由于自发点突变而缺乏功能性GPNMB的DBA/2J小鼠的分析表明，与恢复GPNMB表达的DBA/2J小鼠相比，全身性GPNMB缺乏与MI后心脏功能保留和左心室扩张减轻有关。这些改善与MI后基质金属蛋白酶9、利钠肽（心房利钠肽和脑利钠肽）的心脏应激基因以及β-肌球蛋白重链的表达降低有关。此外，GPNMB缺乏减轻了肌肉lim蛋白敲除小鼠的扩张型心肌病，但不能预防异丙肾上腺素输注诱导的心脏肥大。这是第一项表明GPNMB对心肌重塑产生不利影响的实验研究。-耶尔韦，A.，米尔施泰特，S.，卡德里，F.，尼克l，B.，舒尔茨，H.，许布纳，N.，厄兹切利克，C.，巴德，M.糖蛋白非转移性黑色素瘤蛋白B在心肌梗死中对左心室重塑的不利影响。
