Yaling Han

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

CREG1 (cellular repressor of E1A-stimulated genes 1) is involved in tissue homeostasis and influences macroautophagy/autophagy to protect cardiovascular function. However, the physiological and pathological role of CREG1 in the skeletal muscle is not clear. Here, we established a skeletal muscle-specific creg1 knockout mouse model (creg1;Ckm-Cre) by crossing the Creg1-floxed mice (Creg1^fl/fl) with a transgenic line expressing Cre recombinase under the muscle-specific Ckm (creatine kinase, muscle) promoter. In creg1;Ckm-Cre mice, the exercise time to exhaustion and running distance were significantly reduced compared to Creg1^fl/fl mice at the age of 9 months. In addition, the administration of recombinant (re)CREG1 protein improved the motor function of 9-month-old creg1;Ckm-Cre mice. Moreover, electron microscopy images of 9-month-old creg1;Ckm-Cre mice showed that the mitochondrial quality and quantity were abnormal and associated with increased levels of PINK1 (PTEN induced putative kinase 1) and PRKN/PARKIN (parkin RBR E3 ubiquitin protein ligase) but reduced levels of the mitochondrial proteins PTGS2/COX2, COX4I1/COX4, and TOMM20. These results suggested that CREG1 deficiency accelerated the induction of mitophagy in the skeletal muscle. Mechanistically, gain-and loss-of-function mutations of Creg1 altered mitochondrial morphology and function, impairing mitophagy in C2C12 cells. Furthermore, HSPD1/HSP60 (heat shock protein 1) (401–573 aa) interacted with CREG1 (130–220 aa) to antagonize the degradation of CREG1 and was involved in the regulation of mitophagy. This was the first time to demonstrate that CREG1 localized to the mitochondria and played an important role in mitophagy modulation that determined skeletal muscle wasting during the growth process or disease conditions. Abbreviations: CCCP: carbonyl cyanide m-chlorophenylhydrazone; CKM: creatine kinase, muscle; COX4I1/COX4: cytochrome c oxidase subunit 4I1; CREG1: cellular repressor of E1A-stimulated genes 1; DMEM: dulbecco’s modified eagle medium; DNM1L/DRP1: dynamin 1-like; FCCP: carbonyl cyanide p-trifluoro-methoxy phenyl-hydrazone; HSPD1/HSP60: heat shock protein 1 (chaperonin); IP: immunoprecipitation; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MFF: mitochondrial fission factor; MFN2: mitofusin 2; MYH1/MHC-I: myosin, heavy polypeptide 1, skeletal muscle, adult; OCR: oxygen consumption rate; OPA1: OPA1, mitochondrial dynamin like GTPase; PINK1: PTEN induced putative kinase 1; PPARGC1A/PGC-1α: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; RFP: red fluorescent protein; RT-qPCR: real-time quantitative PCR; SQSTM1/p62: sequestosome 1; TFAM: transcription factor A, mitochondrial; TOMM20: translocase of outer mitochondrial membrane 20; VDAC: voltage-dependent anion channel.

Phenotype switching of cardiac fibroblasts into myofibroblasts plays important role in cardiac fibrosis following myocardial infarction (MI). Cellular repressor of E1A-stimulated genes (CREG) protects against vascular and cardiac remodeling induced by angiotensin-II. However, the effects and mechanisms of CREG on phenotype switching of cardiac fibroblasts after MI are unknown. This study aimed to investigate the role of CREG on the phenotype switching of cardiac fibroblasts following MI and its mechanism. Our findings demonstrated that, compared with littermate control mice, cardiac function was deteriorated in CREG^+/− mice on day 14 post-MI. Fibrosis size, αSMA, and collagen-1 expressions were increased in the border regions of CREG^+/− mice on day 14 post-MI. Conversely, exogenous CREG protein significantly improved cardiac function, inhibited fibrosis, and reduced the expressions of αSMA and collagen-1 in the border regions of C57BL/6J mice on day 14. In vitro, CREG recombinant protein inhibited αSMA and collagen-1 expression and blocked the hypoxia-induced proliferation and migration of cardiac fibroblasts, which was mediated through the inhibition of cell division control protein 42 (CDC42) expression. Our findings could help in establishing new strategies based on the clarification of the role of the key molecule CREG in phenotype switching of cardiac fibroblasts following MI.

Background. Heart failure (HF) is the terminal stage of all cardiovascular events. Although implantable cardioverter defibrillator (ICD) therapies have reduced mortality among the high-risk HF population, it is necessary to determine whether certain factors can predict mortality even after cardiac device implantation. Growth stimulation expressed gene 2 (ST2) is an emerging biomarker for HF patient stratification in different clinical settings. Aims. This study aimed to investigate the relationship between baseline soluble ST2 (sST2) levels in serum and the clinical outcomes of high-risk HF patients with device implantation. Methods. Between January 2017 and August 2018, we prospectively recruited consecutive patients implanted with an ICD for heart failure, with LVEF ≤35% as recommended, and analyzed the basic characteristics, baseline serum sST2, and NT-proBNP levels, with at least 1-year follow-up. All-cause mortality was the primary endpoint. Results. During a 643-day follow-up, all-cause mortality occurred in 16 of 150 patients (10.67%). Incidence of all-cause mortality increased significantly in patients with sST2 levels above 34.98846 ng/ml (16.00% vs. 5.33%, ). After adjusting the model (age, gender, device implantation, prevention of sudden death, LVEDD, LVEF, WBC and CLBBB, hsTNT, etiology, and eGFR) and the model combined with NT-proBNP, the risk of all-cause death was increased by 2.5% and 1.9%, respectively, per ng/ml of sST2. The best sST2 cutoff for predicting all-cause death was 43.42671 ng/ml (area under the curve: 0.72, sensitive: 0.69, and specificity: 0.69). Compared to patients with sST2 levels below 43.42671 ng/ml, the risk of all-cause mortality was higher in those with values above the threshold (5.1% vs. 21.2%, ). ST2 level ≥43.42671 ng/ml was an independent predictor of all-cause mortality (HR: 3.30 [95% CI 1.02–10.67]). Age (HR: 1.06 [95% CI: 1.01–1.12]) and increased NT-proBNP per 100 (HR: 1.02 [95% CI: 1.01–1.03]) were also associated with all-cause mortality in ICD patients. Conclusions. sST2 level was associated with risk of all-cause mortality, and a threshold of 43.43 ng/ml showed good distinguishing performance to predict all-cause mortality in patients with severe heart failure, recommended for ICD implantation. Patients with sST2 levels more than 43.42671 ng/ml even after ICD implantation should therefore be monitored carefully.

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.

Background. Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with high rates of mortality and morbidity. The traditional Chinese medicine Wenxin Keli (WXKL) can effectively improve clinical symptoms and is safe for the treatment of AF. However, the active substances in WXKL and the molecular mechanisms underlying its effects on AF remain unclear. In this study, the bioactive compounds in WXKL, as well as their molecular targets and associated pathways, were evaluated by systems pharmacology. Materials and Methods. Chemical constituents and potential targets of WXKL were obtained via the Traditional Chinese Medicine Systems Pharmacology (TCMSP). The TTD, DrugBank, DisGeNET, and GeneCards databases were used to collect AF‐related target genes. Based on common targets related to both AF and WXKL, a protein interaction network was generated using the STRING database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGGs) pathway enrichment analyses were performed. Network diagrams of the active component‐target and protein‐protein interactions (PPIs) were constructed using Cytoscape. Results. A total of 30 active ingredients in WXKL and 219 putative target genes were screened, including 83 genes identified as therapeutic targets in AF; these overlapping genes were considered candidate targets for subsequent analyses. The effect of treating AF was mainly correlated with the regulation of target proteins, such as IL‐6, TNF, AKT1, VEGFA, CXCL8, TP53, CCL2, MMP9, CASP3, and NOS3. GO and KEGG analyses revealed that these targets are associated with the inflammatory response, oxidative stress reaction, immune regulation, cardiac energy metabolism, serotonergic synapse, and other pathways. Conclusions. This study demonstrated the multicomponent, multitarget, and multichannel characteristics of WXKL, providing a basis for further studies of the mechanism underlying the beneficial effects of WXKL in AF.