Nicotinamide riboside kinase-2 inhibits JNK pathway and limits dilated cardiomyopathy in mice with chronic pressure overload

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 reflected by morphometric parameters as well as increased fetal genes ANP and BNP expressions. Histological assessment revealed an extensive left ventricular (LV) chamber dilatation accompanied by elevated cardiomyopathy 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- induced cardiomyocyte death. Mechanistically, we identified NRK-2 as a regulator of JNK MAP kinase and mitochondrial function where NRK-2 overexpression in human cardiomyocytes markedly suppressed the angiotensin II- induced JNK activation and mitochondrial depolarization. Thus, our results demonstrate that NRK-2 plays protective roles in pressure overload- induced dilatative cardiac remodeling and, genetic ablation exacerbates dilated cardiomyopathy, interstitial collagen deposition, and cardiac dysfunction post-TAC due, in part, to increased JNK activation and mitochondrial dysfunction.

Bioinformatics identifies key genes and potential drugs for energy metabolism disorders in heart failure with dilated cardiomyopathy

“…Transcriptome analysis reveals that NRK and NT5E are upregulated in HF, consistent with existing research ( Ren et al, 2018 ; Byun et al, 2019 ). However, few researchers have explored the upregulation mechanism of NRK in DCM ( Shahzadi et al, 2022 ). Historically, researchers have not paid much attention to the imbalance of NRK and NT5E in HF, as their positive roles implied that attention should be directed towards downregulation.…”

GSK-3α-BNIP3 axis promotes mitophagy in human cardiomyocytes under hypoxia

“…AC16 cells were cultured under conditions previously described [18]. Briefly, the cells were grown in Dulbecco’s Modified Eagle’s Medium/Nutrient Mixture F12 (Sigma-Aldrich, #D6434) supplemented with 2 mM L-glutamine, 10% fetal bovine serum (FBS), and 1% penicillin/streptomycin antibiotic cocktail (Sigma-Aldrich, #P4333).…”

Nicotinamide Riboside, a Promising Vitamin B3 Derivative for Healthy Aging and Longevity: Current Research and Perspectives

“…Thus, NRK2 is reported to limit dilated cardiomyopathy (DCM) in mice with chronic pressure overload (PO). In addition, Ang II-induced cardiomyocyte death is reported to be mitigated by NRK2 overexpression [ 85 ]. NR administration preserves cardiac function in a mouse model of DCM and TAC-induced cardiac hypertrophy, alleviating HF development by stabilizing NAD + levels in the myocardial tissue.…”