Nicotinamide riboside kinase-2 alleviates ischemia-induced heart failure through P38 signaling.
Biochim Biophys Acta Mol Basis Dis
; 1866(3): 165609, 2020 03 01.
Article
em En
| MEDLINE
| ID: mdl-31743747
ABSTRACT
Nicotinamide riboside kinase-2 (NRK-2), a muscle-specific ß1 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-ß stimulation, and limits cardiomyocytes death upon hypoxia/reoxygenation. 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.
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Assunto principal:
Transdução de Sinais
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Isquemia Miocárdica
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Fosfotransferases (Aceptor do Grupo Álcool)
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Sistema de Sinalização das MAP Quinases
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Peptídeos e Proteínas de Sinalização Intracelular
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Insuficiência Cardíaca
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article