The CREG1-FBXO27-LAMP2 axis alleviates diabetic cardiomyopathy by promoting autophagy in cardiomyocytes.

Autophagy plays an important role in the development of diabetic cardiomyopathy. Cellular repressor of E1A-stimulated genes 1 (CREG1) is an important myocardial protective factor. The aim of this study was to investigate the effects and mechanisms of CREG1 in diabetic cardiomyopathy. Male C57BL/6 J mice, Creg1 transgenic mice and cardiac-specific knockout mice were used to establish a type 2 diabetes model. Small animal ultrasound, Masson's staining and western blotting were used to evaluate cardiac function, myocardial fibrosis and autophagy. Neonatal mouse cardiomyocytes (NMCMs) were stimulated with palmitate, and the effects of CREG1 on NMCMs autophagy were examined. CREG1 deficiency exacerbated cardiac dysfunction, cardiac hypertrophy and fibrosis in mice with diabetic cardiomyopathy, which was accompanied by exacerbated autophagy dysfunction. CREG1 overexpression improved cardiac function and ameliorated cardiac hypertrophy and fibrosis in diabetic cardiomyopathy by improving autophagy. CREG1 protein expression was decreased in palmitate-induced NMCMs. CREG1 knockdown exacerbated cardiomyocyte hypertrophy and inhibited autophagy. CREG1 overexpression inhibited cardiomyocyte hypertrophy and improved autophagy. LAMP2 overexpression reversed the effect of CREG1 knockdown on palmitate-induced inhibition of cardiomyocyte autophagy. CREG1 inhibited LAMP2 protein degradation by inhibiting the protein expression of F-box protein 27 (FBXO27). Our findings indicate new roles of CREG1 in the development of diabetic cardiomyopathy.

Corrigendum to "Orosomucoid 1 Attenuates Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes via Nrf2 Signaling".

[This corrects the article DOI: 10.1155/2020/5923572.].

Orosomucoid 1 Attenuates Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes via Nrf2 Signaling.

Doxorubicin (DOX) is an effective anticancer drug, but its therapeutic use is limited by its cardiotoxicity. The principal mechanisms of DOX-induced cardiotoxicity are oxidative stress and apoptosis in cardiomyocytes. Orosomucoid 1 (ORM1), an acute-phase protein, plays important roles in inflammation and ischemic stroke; however, the roles and mechanisms of ORM1 in DOX-induced cardiotoxicity remain unknown. Therefore, in the present study, we aimed to investigate the function of ORM1 in cardiomyocytes experiencing DOX-induced oxidative stress and apoptosis. A DOX-induced cardiotoxicity animal model was established in C57BL/6 mice by administering an intraperitoneal injection of DOX (20 mg/kg), and the control group was intraperitoneally injected with the same volume of sterilized saline. The effects were assessed after 7 d. Additionally, H9c2 cells were stimulated with DOX (10 µM) for 24 h. The results showed decreased ORM1 and increased oxidative stress and apoptosis after DOX stimulation in vivo and in vitro. ORM1 overexpression significantly reduced DOX-induced oxidative stress and apoptosis in H9c2 cells. ORM1 significantly increased the expression of nuclear factor-like 2 (Nrf2) and its downstream protein heme oxygenase 1 (HO-1) and reduced the expression of the lipid peroxidation end product 4-hydroxynonenal (4-HNE) and the level of cleaved caspase-3. In addition, Nrf2 silencing reversed the effects of ORM1 on DOX-induced oxidative stress and apoptosis in cardiomyocytes. In conclusion, ORM1 inhibited DOX-induced oxidative stress and apoptosis in cardiomyocytes by regulating the Nrf2/HO-1 pathway, which might provide a new treatment strategy for DOX-induced cardiotoxicity.

Lycium barbarum polysaccharides protect mice from hyperuricaemia through promoting kidney excretion of uric acid and inhibiting liver xanthine oxidase.

CONTEXT: Lycium barbarum L. (Solanaceae) polysaccharides (LBPs) are important active constituents that have demonstrated kidney protection. OBJECTIVE: This study investigated the effect of LBPs on hyperuricaemia and explored the underlying mechanism in mice. MATERIALS AND METHODS: Thirty-six C57BL/6 mice were randomly divided into the control group, hyperuricaemia group, allopurinol group (5 mg/kg) and three LBP groups (n = 6). The LBP groups were treated orally with LBPs at 50, 100 and 200 mg/kg body weight for 7 days. We examined the levels of serum uric acid (SUA) and urinary uric acid (UUA), as well as xanthine oxidase (XOD) activities. mRNA and protein were quantified by quantitative real-time PCR and Western blotting, respectively. RESULTS: LBPs treatment (100 and 200 mg/kg) significantly reduced the SUA levels to 4.83 and 4.48 mg/dL, and markedly elevated the UUA levels to 4.68 and 5.18 mg/dL (p < 0.05), respectively, while significantly increased the mRNA and protein expression levels of renal organic anti-transporter 1 (OAT1) and organic anti-transporter 3 (OAT3), and markedly decreased the levels of glucose transporter 9 (GLUT9) (p < 0.05). Additionally, the serum XOD activities were reduced to 31.5 and 31.1 mU/mL, and the liver XOD activities were reduced to 80.6 and 75.6 mU/mL after treatment with 100 and 200 mg/kg LBPs (p < 0.01), respectively. DISCUSSION AND CONCLUSIONS: This study demonstrated the potential role of LBPs in reducing the uric acid level in hyperuricemic mice. A border study population should be evaluated. These results are valuable for the development of new anti-hyperuricaemia agents from LBPs.

Low-dose nicotine promotes autophagy of cardiomyocytes by upregulating HO-1 expression.

Nicotine as a major component of addiction in cigarettes has been reported to play protective roles in some pathological processes. It is reported that activation of the nicotinic acetylcholine receptor also has a cardioprotective effect. Thus, in our study, we investigated the effect and mechanism of nicotine on the autophagy of cardiomyocytes, and whether nicotine protects cardiomyocytes against palmitic acid (PA) injury. The results indicated that low-dose nicotine promoted neonatal mouse cardiac myocytes (NMCMs) autophagy and accelerated autophagic flux while inhibiting NMCMs apoptosis, but high-dose nicotine inhibited autophagy and promoted apoptosis. Moreover, low-dose nicotine upregulated heme oxygenase-1 (HO-1) expression and knocking down HO-1 abolished the effects of nicotine on the autophagy and apoptosis of NMCMs. Methyllycaconitine citrate (α7-nAChR blocker, MLA) inhibited HO-1 expression and the effects of nicotine on autophagy and apoptosis of NMCMs. Furthermore, low-dose nicotine improved the inhibited autophagy and increased apoptosis induced by palmitic acid (PA) in NMCMs and these effects were reversed by knocking down HO-1. In conclusion, our data suggested that low-dose nicotine promoted autophagy and inhibited apoptosis of cardiomyocytes by upregulating HO-1.

MiR-207 inhibits autophagy and promotes apoptosis of cardiomyocytes by directly targeting LAMP2 in type 2 diabetic cardiomyopathy.

Autophagy dysfunction plays a critical role in diabetic cardiomyopathy (DCM). MiR-207 regulates the expression of lysosomal-associated membrane protein 2 (LAMP2), an autophagy-related protein, following ischemic stroke in neurocytes. However, the roles and mechanisms of miR-207 in DCM remain unknown. Therefore, in this study, we aim to investigate the roles and mechanisms of miR-207 in type 2 DCM. The results showed that autophagic dysfunction with increased LC3II and P62 expression and decreased LAMP2 expression, and increased cell apoptosis with up-regulated cleaved-caspase3 expression were noted in the myocardium of type 2 DCM mice and neonatal mouse cardiac myocytes (NMCMs) stimulated with PA. In addition, miR-207 was significantly upregulated in the myocardium of DCM mice and NMCMs stimulated with PA. In NMCMs, miR-207 inhibited LAMP2 mRNA and protein expression. MiR-207 mimics significantly inhibited autophagy by increasing P62 and LC3II expression and promoted cell apoptosis by increasing cleaved-caspase3 expression, and these effects were reversed by LAMP2 overexpression. In conclusion, miR-207 inhibited autophagy and promoted apoptosis of cardiomyocytes by directly targeting LAMP2, which participated in the development of type 2 diabetic cardiomyopathy.