Nicotinamide riboside kinase-2 inhibits JNK pathway and limits dilated cardiomyopathy in mice with chronic pressure overload.
Clin Sci (Lond)
; 136(2): 181-196, 2022 01 28.
Article
em En
| MEDLINE
| ID: mdl-35048952
ABSTRACT
Nicotinamide riboside kinase-2 (NRK-2) has recently emerged as a critical regulator of cardiac remodeling however, underlying molecular mechanisms is largely unknown. To explore the same, NRK2 knockout (KO) and littermate control mice were subjected to trans-aortic constriction (TAC) or sham surgeries and cardiac function was assessed by serial M-mode echocardiography. A mild cardiac contractile dysfunction was observed in the KOs at the early adaptive phase of remodeling followed by a significant deterioration during the maladaptive cardiac remodeling phase. Consistently, NRK2 KO hearts displayed increased cardiac hypertrophy and heart failure (HF) reflected by morphometric parameters as well as increased fetal genes, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expressions. Histological assessment revealed an extensive left ventricular (LV) chamber dilatation accompanied by elevated cardiomyopathy (CM) and fibrosis in the KO hearts post-TAC. In a gain-of-function model, NRK-2 overexpressing in AC16 cardiomyocytes displayed significantly attenuated fetal genes ANP and BNP expression. Consistently, NRK-2 overexpression attenuated angiotensin II (Ang II)-induced cardiomyocyte death. Mechanistically, we identified NRK-2 as a regulator of c-jun N-terminal kinase (JNK) MAP kinase and mitochondrial function where NRK-2 overexpression in human cardiomyocytes markedly suppressed the Ang II-induced JNK activation and mitochondrial depolarization. Thus, our results demonstrate that NRK-2 plays protective roles in pressure overload (PO)-induced dilatative cardiac remodeling and, genetic ablation exacerbates dilated cardiomyopathy (DCM), interstitial collagen deposition, and cardiac dysfunction post-TAC due, in part, to increased JNK activation and mitochondrial dysfunction.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cardiomiopatia Dilatada
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Fosfotransferases (Aceptor do Grupo Álcool)
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Sistema de Sinalização das MAP Quinases
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Clin Sci (Lond)
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Emirados Árabes Unidos