Nicotinamide riboside kinase-2 (NRK-2), a muscle-specific β1 integrin binding protein, predominantly expresses in skeletal muscle with a trace amount expressed in healthy cardiac tissue. NRK-2 expression dramatically increases in mouse and human ischemic heart however, the specific role of NRK-2 in the pathophysiology of ischemic cardiac diseases is unknown. We employed NRK2 knockout (KO) mice to identify the role of NRK-2 in ischemia-induced cardiac remodeling and dysfunction. Following myocardial infarction (MI), or sham surgeries, serial echocardiography was performed in the KO and littermate control mice. Cardiac contractile function rapidly declined and left ventricular interior dimension (LVID) was significantly increased in the ischemic KO vs. control mice at 2 weeks post-MI. An increase in mortality was observed in the KO vs. control group. The KO hearts displayed increased cardiac hypertrophy and heart failure reflected by morphometric analysis. Consistently, histological assessment revealed an extensive and thin scar and dilated LV chamber accompanied with elevated fibrosis in the KOs post-MI. Mechanistically, we observed that loss of NRK-2 enhanced p38α activation following ischemic injury. Consistently, ex vivo studies demonstrated that the gain of NRK-2 function suppresses the p38α as well as fibroblast activation (α-SMA expression) upon TGF-β stimulation, and limits cardiomyocytes death upon hypoxia/re‑oxygenation. Collectively our findings show, for the first time, that NRK-2 plays a critical role in heart failure progression following ischemic injury. NRK-2 deficiency promotes post-MI scar expansion, rapid LV chamber dilatation, cardiac dysfunction and fibrosis possibly due to increased p38α activation.

中文翻译：

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烟酰胺核糖苷激酶2通过P38信号传导减轻缺血性心力衰竭。

烟酰胺核糖核苷激酶2（NRK-2）是一种肌肉特异性的β1整联蛋白结合蛋白，主要在骨骼肌中表达，并在健康的心脏组织中表达。NRK-2表达在小鼠和人类缺血性心脏中显着增加，但是，NRK-2在缺血性心脏病的病理生理中的具体作用尚不清楚。我们采用了NRK2基因敲除（KO）小鼠来鉴定NRK-2在缺血诱导的心脏重塑和功能障碍中的作用。心肌梗塞（MI）或假手术后，在KO和同窝对照小鼠中进行连续超声心动图检查。MI后2周，缺血性KO与对照组小鼠的心脏收缩功能迅速下降，左室内部尺寸（LVID）显着增加。与对照组相比，在KO中观察到死亡率增加。通过形态计量学分析，KO心脏显示出心脏肥大和心力衰竭增加。一致的是，组织学评估显示，MI后KO中广泛而稀薄的疤痕和左室扩张，并伴有纤维化升高。从机理上讲，我们观察到NRK-2的缺失增强了缺血性损伤后p38α的活化。一致地，离体研究表明，在TGF-β刺激下，NRK-2功能的获得抑制了p38α和成纤维细胞的活化（α-SMA表达），并限制了缺氧/复氧后心肌细胞的死亡。总的来说，我们的发现首次表明NRK-2在缺血性损伤后的心力衰竭进展中起着至关重要的作用。NRK-2缺乏症会促进心肌梗死后瘢痕的扩展，左室快速扩张，