葛毅萍
青岛大学附属医院 小儿内科
Doxorubicin (DOX) is an antineoplastic agent that is widely employed in carcinomas, but it can cause cardiotoxicity in clinic. TRIM25 has E3 ubiquitin ligase activities and can ubiquitinate its target proteins. The role of TRIM25 in DOX-induced cardiotoxicity remains unknown. In this study, our results showed that DOX induced pyroptosis of H9c2 cells by TUNEL staining and Western blot assay. Interestingly, TRIM25 was downregulated in DOX-treated H9c2 cells in a time- and dose-dependent manner. TRIM25 attenuated DOX-induced pyroptosis of H9c2 cells. Furthermore, in vitro ubiquitination assay proved that TRIM25 decreased the stability of NLRP1 via promoting the ubiquitination of NLRP1. The rescue experiments confirmed that TRIM25 inhibited DOX-induced H9c2 cells pyroptosis by regulating NLRP1 stability. Animal experiments demonstrated that overexpression of TRIM25 attenuated DOX-induced cardiomyocyte pyroptosis in rats. In summary, TRIM25 exerts its cardioprotective effects by promoting the ubiquitination of NLRP1 in DOX-induced cardiomyocyte pyroptosis, which provides a novel therapeutic strategy for DOX-induced cardiotoxicity.
Cardiovascular toxicology 2021
OBJECTIVE:To compare the accuracy of five warfarin-dosing algorithms and warfarin stable dose model (2.5 mg/day) for Shandong population.METHODS:One hundred and twenty five patients who achieved stable warfarin dose were enrolled. Clinical and genetic data were used to evaluate the value of each algorithm by calculating the percentage of patients whose predicted warfarin dose was within 20% of the actual stable therapeutic dose and mean absolute error (MAE).RESULTS:The frequency of patients with CYP2C9*1/*1, CYP2C9*1/*3 and CYP2C9*1/*2 genotype was 92.00%, 7.20%, 0.80%, respectively. That of VKORC1-1639 AA, AG and GG genotype was 82.40%, 15.20%, 2.40%, respectively. CYP4F2*1/*1, *1/*3, *3/*3 genotype was 50.40%, 39.20%, 10.40%, respectively. With the same genotypes for other loci, patients who carried at least one VKORC1-16398G mutant allele had increased warfarin stable daily dose compared with VKORC1-1639AA. Compared with CYP4F2*1/*1, those carrying at least one CYP4F2*3 mutant allele had warfarin stable daily dose increased by 5.9%-13.00%. The percentage of ideal prediction calculated from IWPC model (59.20%), Huang model (57.60%) and Ohno model (52.80%) were higher than others. The MAE were 0.35 (95%CI: 0.11-0.49), 0.15 (95%CI: 0.10-0.32), 0.39 (95%CI: 0.12-0.51), respectively.CONCLUSION:The polymorphisms of CYP2C9, VKORC1 and CYP4F2 genes can influence the stable dose of warfarin in Shandong population. IWPC algorithm is suitable for guiding the use of warfarin in this population.
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2020
Heart failure (HF) is an end-stage of various serious cardiovascular diseases, which causes liver injury. Hyperoside has been reported to exert protective effect on liver injury and fibrosis. However, the role and related mechanisms of hyperoside in HF-induced liver fibrosis are still unclear. In the current study, we established a model of HF via aortocaval fistula (ACF) in rats in vivo. Hyperoside treatment in ACF rats increased cardiac output, the maximum peak rate of rise/fall in left ventricular pressure (+dP/dt, -dP/dt) and LV ejection fraction (LVEF), decreased LV end-systolic pressure (LVESP), LV end-diastolic pressure (LVEDP) and LV end-systolic volume (LVESV), and reduced heart weight/body weight ratio in a dose-dependent manner. Moreover, hyperoside could attenuate liver fibrosis and injury in ACF rats, as evidenced by reduction of fibrosis area and hydroxyproline content, amelioration of edema and degeneration of liver cell vacuoles, and inhibition of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels. Further, α-smooth-muscle actin (α-SMA), collagen I, profibrotic factor-connective tissue growth factor (CTGF), matrix metalloproteinase-2 (MMP2) and MMP9 levels were down-regulated in hyperoside-treated ACF rats. Additionally, hyperoside inhibited the activation of TGF-β1/Smad pathway. Finally, we confirmed that hyperoside suppressed TGF-β1-mediated hepatic stellate cell activation in vitro. Collectively, hyperoside showed a suppressive role in HF-induced liver fibrosis and injury.
Acta histochemica 2019
Aim: To observe if personalized antiplatelet therapy according to the CYP2C19 phenotype can improve the outcomes of patients receiving selective percutaneous coronary intervention (PCI). Methods: In this observational study, 677 Chinese patients undergoing selective PCI were divided into gene group (n = 369) and conventional group (n = 308), and given antiplatelet therapy according to the CYP2C19 genotype or clinical features, respectively. Incidence of MACE (death, non-fatal myocardial infarction, and unplanned repeat revascularization) and bleeding was compared between the two groups after 18 months. Results: Diabetes, heart dysfunction and SYNTAX score (>15), but not routinely CYP2C19 genotype test-guided antiplatelet therapy, were associated with MACE. The incidence of bleeding showed no difference. Conclusion: CYP2C19 phenotype-guided antiplatelet therapy may have no influence on the outcomes of selective PCI patients. Clinical features-guided antiplatelet therapy may be reasonable.
Personalized medicine 2019
Hypertension is a universal risk factor for a variety of cardiovascular diseases. Investigation of the mechanism for hypertension will benefit around 40% of the world's adult population. MicroRNA is crucial for the initiation and progression of cardiovascular diseases. In this study, angiotensin II-treated human umbilical vein endothelial cells were used as a model to imitate the pathological changes in endothelial cells under hypertensive conditions. We demonstrated that microRNA-9 (miR-9) suppressed angiotensin II-induced apoptosis and enhanced proliferation in human umbilical vein endothelial cells. Direct interaction between miR-9 and mitochondria associated membrance domain containing glycosylphosphatidylinositol anchor 2 (MDGA2) was determined. Moreover, miR-9 suppressed MDGA2 levels by binding to the 3' UTR site of the MDGA2 gene. This negative regulation of MDGA2 by miR-9 significantly increased proliferation and decreased apoptosis. Re-introduction of MDGA2 in the miR-9 overexpressed human umbilical vein endothelial cells and normalized proliferation, apoptosis, and the cell cycle. In summary, the present study demonstrated miR-9 inhibited expression of MDGA2 leading to the inhibition of apoptosis and promotion of proliferation in angiotensin II-treated human umbilical vein endothelial cells.
Reviews in cardiovascular medicine 2019
OBJECTIVE:To explore the effects of gender on treatment strategies for elderly patients with acute coronary syndrome (ACS).METHODS:March 2009 to March 2012, consecutive 619 aged ACS patients undergoing coronary angiography (CA) were screened at our hospital. There were 273 females and 346 males. Risk factors, ACS diagnosis, CA results, treatments and prognosis were compared between female and male groups.RESULTS:The risk factors of body mass index, stroke history, smoking history, hemoglobin (Hb), serum cholesterol (TC), low density lipoprotein (LDL-C) and blood uric acid (UA) levels were significantly lower in female group than those in male group (P < 0.05). The morbidity of diabetes in female group was obviously higher than that in male group (27.8% vs 18.5%, P < 0.05). The prevalence of myocardial infarction history, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) history in male group were significantly greater than that in female group (48.0% vs 39.9%, P < 0.05; 30.6% vs 22.3%, P < 0.05; 19.9% vs 10.3%, P < 0.01). The rate of combined multiple risk factors (3 or higher) increased significantly in female group (41.8% vs 29.8%, P < 0.05). The incidence of unstable angina pectoris (UAP) and non-ST segment elevation myocardial infarction (NSTEMI) in female group was greater, but there was no statistical significance. The rate of 3-vessel and calcification lesions in female group was significantly elevated compared with male group (36.26% vs 28.61%, P < 0.05). Regarding the choice of treatment strategy, conservative treatment was common in females, but there was no statistical significance between them. PCI, emergency PCI and selective CABG operation were performed more frequently in female group compared with male group (26.0% vs 14.2%, P < 0.01; 14.7% vs 6.6%, P < 0.01; 19.1% vs 7.7%, P < 0.01). The prognosis had no statistical significance between two groups.CONCLUSION:The treatment strategies have certain limitations for female ACS patients. And an more aggressive treatment should be offered to improve the prognosis.
Zhonghua yi xue za zhi 2013
