ABHD15 promotes cell viability, glycolysis, and inhibits apoptosis in cardiomyocytes under hypoxia.

BACKGROUND AND AIMS: Myocardial infarction (MI) has been an important heart disease affecting human health. The aim of this study was to investigate the regulatory effect of abhydrolase domain containing 15 (ABHD15) on hypoxic cardiomyocytes. METHODS AND RESULTS: Hypoxic cardiomyocytes are commonly used as an vitro model for the study of MI. We found that cardiomyocyte viability was decreased under hypoxia, but cell glucose uptake, insulin receptor phosphorylation level and apoptosis were increased. Interestingly, ABHD15 expression was up-regulated in hypoxia-induced cardiomyocytes. Then, we identified the function of ABHD15 in hypoxic cardiomyocytes by using ABHD15 overexpression vector or short interfering RNA (siRNA) against ABHD15. The results showed that overexpression of ABHD15 promoted hypoxic cardiomyocyte viability, glucose uptake and IR phosphorylation (p-IR), and inhibited cell apoptosis. However, knockdown of ABHD15 attenuated hypoxic cardiomyocyte viability, glucose uptake and IR phosphorylation, and promoted apoptosis. Moreover, we found that ABHD15 promoted glucose transporter 4 (GLUT4) expression, translocation and enhance rate-limiting enzyme activation of glycolysis, thereby affecting glucose uptake. Furthermore, our study suggested that ABHD15 may affect the viability and apoptosis of hypoxic cardiomyocytes through IR/Ras/Raf/ERK/MEK and IR/PI3K/AKT/Bcl2/Bad/caspase9 signaling pathways, respectively. When the phosphorylation of IR, Raf or ERK was blocked by inhibitors, the protective effect of overexpressing ABHD15 on the viability of hypoxic cardiomyocytes was eliminated. Furthermore, inhibiting the phosphorylation of IR, AKT or Bcl2 abolished the inhibitory effect of overexpressing ABHD15 on hypoxic cardiomyocyte apoptosis. CONCLUSION: ABHD15 regulated myocardial cell viability, glycolysis, and apoptosis under hypoxia, providing a novel potential therapeutic strategy for MI.

Interleukin-5 deletion promotes sepsis-induced M1 macrophage differentiation, deteriorates cardiac dysfunction, and exacerbates cardiac injury via the NF-κB p65 pathway in mice.

Inflammation plays a crucial role in sepsis-induced cardiac injury. The purpose of this study was to determine whether interleukin-5 (IL-5) affected lipopolysaccharide (LPS)-induced cardiac injury by regulating the inflammatory response. First, the expression level and source of cardiac IL-5 were examined, and the results showed that LPS treatment and cecal ligation decreased cardiac IL-5 expression in macrophages. In addition, LPS was used to establish a mouse sepsis model, and the effects of IL-5 deletion on cardiac injury, M1 macrophage differentiation and myocardial cell apoptosis were analyzed. The results showed that IL-5 deficiency significantly increased cardiac injury marker expression, worsened cardiac dysfunction, promoted M1 macrophage differentiation and exacerbated myocardial cell apoptosis in LPS-induced septic mice. The nuclear factor-kappa B (NF-κB) p65 pathway was inhibited by JSH-23, and the results showed that treatment with JSH-23 inhibited M1 macrophage differentiation and alleviated cardiac injury in LPS-treated IL-5-knockout mice. Furthermore, the effects of IL-5 deficiency on M1 macrophage differentiation and myocardial cell apoptosis were measured in vitro. The IL-5-mediated promotion of M1 macrophage differentiation was also reversed by S31-201, and the pro-apoptotic effect of IL-5 knockout on macrophage-mediated myocardial cell apoptosis was also reversed by JSH-23. In conclusion, we found that IL-5 knockout may exacerbate sepsis-induced cardiac injury by promoting M1 macrophage differentiation in mice. IL-5 may be a potential target for the clinical prevention of sepsis-related cardiac injury.

WITHDRAWN: Schisandrin B suppresses NLRP3 inflammasome activation to alleviate myocardial ischemia reperfusion injury via maintaining mitochondrial autophagy.

This article has been retracted at the request of the authors. The Editor in Chief has agreed to retract this article and the publisher supports the decision. The authors have indicated that their initial results were not reproducible when conducted by their colleagues. They indicated that the levels of autophagy were significantly different in the MI/R mice model in the respective results. The authors of this article would like to apologize to all affected parties. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Barbaloin pretreatment attenuates myocardial ischemia-reperfusion injury via activation of AMPK.

Myocardial ischemia/reperfusion (MI/R) injury is a major cause of cardiac dysfunction during cardiovascular surgery and heart transplantation and characterized by hyperactive oxidative stress and inflammatory response. Barbaloin (BAR) is the main medicinal composition of the Chinese traditional medicine aloe vera. BAR has strong anti-oxidant, anti-inflammatory and anti-tumor properties. However, the effect of BAR on MI/R-induced myocardial injury is not explored. This study aims to investigate whether BAR provides cardio-protection against MI/R injury and the underlying mechanisms. BAR (20 mg/kg/d) or vehicle was intragastrically administered to Sprague-Dawley rats for 5 days before MI/R operation. BAR pretreatment conferred cardio-protective effects against MI/R injury by improving hemodynamic function and limiting infarction size. Moreover, BAR pretreatment effectively inhibited I/R-induced myocardial oxidative stress and inflammatory response. Furthermore, BAR pretreatment activated adenosine monophosphate-activated protein kinase (AMPK) signaling in MI/R hearts. AMPK inhibitor compound C inhibited BAR-induced AMPK activation, and blunted BAR-mediated anti-oxidative, anti-inflammatory effects and cardio-protection. Taken together our study has identified a novel function of BAR and provided a molecular basis for BAR potential applications in the treatment of MI/R injury and other ischemic disorders.

NDUFA4L2 protects against ischaemia/reperfusion-induced cardiomyocyte apoptosis and mitochondrial dysfunction by inhibiting complex I.

Myocardial ischaemia/reperfusion (I/R) injury may cause the apoptosis of cardiomyocytes as well as mitochondrial dysfunction. The aims of the present study were to investigate whether NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2) on myocardial ischaemia-reperfusion (I/R) injury and the underlying molecular mechanism. The hypoxia-reperfusion (H/R) model was established in vitro using H9c2 cells to simulate I/R injury. NDUFA4L2 and complex I expression levels were detected using RT-PCR and western blot. The apoptosis of H9c2 cells was evaluated by flow cytometry and the expression of Bax and Bcl-2 was detected by western blot. The mitochondrial function was assessed by ATP concentration, mPTP opening and cytochrome c (cyto C) expression. Our data indicated that NDUFA4L2 expression was significantly down-regulated in myocardial H/R injury. Overexpression of NDUFA4L2 led to a dramatic prevention of H/R-induced apoptosis accompanied by a decrease in the expression of Bax and an increase in the expression of Bcl-2. Meanwhile, augmentation of NDUFA4L2 dramatically prevented mitochondrial dysfunction caused by H/R as reflecting in the increased ATP concentration, delayed mPTP opening, as well as down-regulated cyto C expression. Moreover, complex I activation was heightened and negatively regulated by NDUFA4L2. Silencing complex I conspicuously attenuated cell apoptosis and mitochondrial dysfunction. Taken together, our findings demonstrated that NDUFA4L2 protects against H/R injury by preventing myocardium apoptosis and mitochondrial dysfunction via the complex I, and may be a potential therapeutic approach for attenuating myocardial I/R injury.

Downregulation of miR-122 attenuates hypoxia/reoxygenation (H/R)-induced myocardial cell apoptosis by upregulating GATA-4.

MicroRNA-122 has been reported to play a potential role in the apoptosis of myocardial cells. However, the effect of miR-122 in regulating myocardial ischemic injury has not been previously addressed. This study aimed to investigate the effect and the molecular basis of miR-122 on myocardial ischemic injury. Using the hypoxia/reoxygenation (H/R) model of rat cardiomyocytes H9C2 in vitro, we found that miR-122 was highly expressed in H9C2 cells after H/R treatment. Overexpression of miR-122 by recombinant adeno-associated viral vector infection markedly promoted the apoptosis of H9C2 cells induced by H/R treatment, whereas miR-122 inhibition significantly decreased cell apoptosis. Dual-luciferase reporter assay and western blot assay revealed that GATA-4 was a direct target gene of miR-122, and miR-122 suppressed the expression of GATA-4 via binding to its 3'-UTR. We further identified that overexpression of miR-122 inhibited the expression of GATA-4 at the mRNA and protein levels, whereas the inhibition of miR-122 upregulated the expression of GATA-4. Moreover, GATA-4 was poorly expressed in H/R H9C2 cells and the apoptosis induced by H/R was associated with the decrease in GATA-4 expression. Importantly, silencing of GATA-4 apparently abrogated the inhibitory effect of anti-miR-122 on H/R-induced cell apoptosis. In conclusion, these findings indicate that downregulation of miR-122 alleviates cardiomyocyte H/R injury through upregulation of GATA-4 expression, supplying a novel molecular target for myocardial ischemic injury.