Critical role of X-box binding protein 1 in NADPH oxidase 4-triggered cardiac hypertrophy is mediated by receptor interacting protein kinase 1

Abstract

NADPH oxidase 4 (NOX4) and the NOX4-related redox signaling are implicated in cardiac hypertrophy. NOX4 is interrelated with endoplasmic reticulum stress (ERS). Spliced X-box binding protein 1 (Xbp1s) is a key mediator of ERS while its role in cardiac hypertrophy is still poorly understood. Recently, receptor interacting protein kinase 1(RIPK1) has been increasingly reported to be associated with ERS. Therefore, we aimed to test the hypothesis that Xbp1s mediates NOX4-triggered cardiac hypertrophy via RIPK1 signaling. In the heart tissue of transverse aortic constriction (TAC) rats and in primary cultured neonatal cardiomyocytes(NCMs) treated with angiotensinII(AngII) or isoproterenol (ISO), NOX4 expression and reactive oxygen species (ROS) generation, and expression of Xbp1s as well as RIPK1-related phosphorylation of P65 subunit of NF-kB were elevated. Gene silencing of NOX4 by specific small interfering RNA (siRNA) significantly blocked the upregulation of NOX4, generation of ROS, splicing of Xbp1 and activation of the RIPK1-related NF-kB signaling, meanwhile attenuated cardiomyocyte hypertrophy. In addition, ROS scavenger (N-acetyl-L-cysteine, NAC) and NOX4 inhibitor GKT137831 reduced ROS generation and alleviated activation of Xbp1 and RIPK1-related NF-kB signaling. Furthermore, splicing of Xbp1 was responsible for the increase in RIPK1 expression in AngII or ISO-treated NCMs. Upregulated RIPK1 in turn activates NF-kB signaling in a kinase activity-independent manner. These findings suggest that Xbp1s plays an important role in NOX4-triggered cardiomyocyte hypertrophy via activating its downstream effector RIPK1, which may prove significant for the development of future therapeutic strategies. KEYWORDS cardiac hypertrophy; endoplasmic reticulum stress; NADPH oxidase 4; receptor interacting protein kinase 1; X-box binding protein 1

Inhibition of Mitofusin-2 Promotes Cardiac Fibroblast Activation via the PERK/ATF4 Pathway and Reactive Oxygen Species

“…Firstly, we evaluated the change of Mfn2 expression in TAC rats compared with that in sham-operated rats. Echocardiography indicators and HE staining suggested that cardiac hypertrophy is induced by the TAC model successfully in our previous papers [11, 18]. As shown in Figure 1(a), the left ventricular weight to body weight (HW/BW) (mg/g) ratio also implied that cardiac hypertrophy was induced in TAC models.…”

“…Intracellular ROS production was determined by oxidative conversion of cell-permeable 20,70-dichlorofluorescein diacetate (H2DCFDA) (Sigma-Aldrich) to fluorescent dichlorofluorescein [11]. Cardiac fibroblasts were washed with serum-free DMEM and incubated with H2DCFDA (10 mM) for 60 min at 37°C in an incubator.…”

“…Our previous work has identified that ER stress and ROS are important mechanisms involved in cardiac hypertrophy [11–13]. ER stress is defined as the accumulation of misfolded proteins within the ER lumen, initiating three major pathways to restore ER homeostasis.…”

Protective Effect of Unacylated Ghrelin on Compression-Induced Skeletal Muscle Injury Mediated by SIRT1-Signaling

“…Our data indicated that the interaction of UnAG with SIRT1 might play a role in coordinating necroptosis during pressure-induced tissue injury, suggesting that SIRT1 might be able to serve as the potential molecular target for further unraveling the pathogenesis of pressure ulcers as well as the myoprotective effect of UnAG in pressure ulcers. Chen et al ( 2017 ) revealed recently that NADPH oxidase 4 (NOX4) increased the expression of RIPK1 and simultaneously activated nuclear factor kappa B (NF-kB) via increased phosphorylation of p65 subunit of NF-kB, in the heart tissue of transverse aortic constriction rats. Notably, gene silencing of NOX4 by specific siRNA effectively opposed the upregulation of RIPK1 and phosphorylation of p65 subunit of NF-kB, suggesting that NOX4 might be required for the activation of necroptosis and NF-kB signaling pathways (Chen et al, 2017 ).…”

“…Chen et al ( 2017 ) revealed recently that NADPH oxidase 4 (NOX4) increased the expression of RIPK1 and simultaneously activated nuclear factor kappa B (NF-kB) via increased phosphorylation of p65 subunit of NF-kB, in the heart tissue of transverse aortic constriction rats. Notably, gene silencing of NOX4 by specific siRNA effectively opposed the upregulation of RIPK1 and phosphorylation of p65 subunit of NF-kB, suggesting that NOX4 might be required for the activation of necroptosis and NF-kB signaling pathways (Chen et al, 2017 ). Resveratrol, the potent SIRT1 agonist, suppressed NOX4 upregulation in the muscle of dystrophin-deficient mice, whereas SIRT1 knockdown in cultured C2C12 myoblasts resulted in NOX4 protein upregulation (Hori et al, 2011 ).…”