Downregulation of miR-181a-5p alleviates oxidative stress and inflammation in coronary microembolization-induced myocardial damage by directly targeting XIAP.

BACKGROUND: Coronary microembolization (CME) is a complicated problem that commonly arises in the context of coronary angioplasty. MicroRNAs play crucial roles in cardiovascular diseases. However, the role and mechanism of miR-181a-5p in CME-induced myocardial injury remains unclear. METHODS: We established CME rat models. Cardiac function was detected by echocardiography. Haematoxylin-basic fuchsin-picric acid staining was used to measure micro-infarction size. Serum samples and cell culture supernatants were evaluated via enzyme-linked immunosorbent assay. Cellular reactive oxygen species were determined by dichloro-dihydro-fluorescein diacetate assay, and the other oxidative stress related parameters were assayed by spectrophotometry. The dual-luciferase reporter (DLR) assay and RNA pulldown were conducted to validate the association between miR-181a-5p and X-linked inhibitor of apoptosis protein (XIAP). The expression of miR-181a-5p and XIAP mRNA were determined by quantitative reverse transcription polymerase chain reaction. Proteins were evaluated via immunoblotting. The viability of the cell was evaluated via cell counting kit-8 assay. RESULTS: The miR-181a-5p level was significantly increased in CME myocardial tissues. Downregulation of miR-181a-5p improved CME-induced cardiac dysfunction and alleviated myocardial oxidative stress and inflammatory injury, whereas miR-181a-5p exhibited the opposite effects. Then, the DLR assay and RNA pulldown results revealed that miR-181a-5p directly targeting on XIAP. The XIAP level was found to be remarkably decreased after CME. XIAP overexpression attenuated CME-induced myocardial oxidative stress and inflammatory injury. Finally, in vitro rescue experiments revealed that knockdown of XIAP could abolish the protective effects of miR-181a-5p knockdown on hypoxia-induced cardiomyocyte oxidative stress and inflammatory injury. CONCLUSIONS: Downregulation of miR-181a-5p alleviates CME-induced myocardial damage by suppressing myocardial oxidative stress and inflammation through directly targeting XIAP.

Ischemia/hypoxia inhibits cardiomyocyte autophagy and promotes apoptosis via the Egr-1/Bim/Beclin-1 pathway.

BACKGROUND: Myocardial injury caused by microvascular obstruction (MVO) is characterized by persistent ischemia/hypoxia (IH) of cardiomyocytes after microembolization. Autophagy and Egr-1 were closely associated with various cardiovascular diseases, including MVO. Bim and Beclin-1 are the important genes for autophagy and apoptosis. We aimed to explore whether the Egr-1/Bim/Beclin-1 pathway is involved in regulating autophagy and apoptosis in IH-exposed cardiomyocytes. METHODS: Neonatal rat cardiomyocytes exposed to the IH environment in vitro were transfected with lentivirus expressing Egr-1 or Egr-1 shRNA, or further treated with 3-methyladenine (3-MA). The expressions of autophagy and apoptosis-associated genes were evaluated using RT-qPCR and Western blots assays. Autophagic vacuoles and autophagic flux were detected by transmission electron microscopy (TEM) and confocal microscope, respectively. Cell injury was assessed by lactate dehydrogenase (LDH) leakage, and apoptosis was determined by flow cytometry. RESULTS: IH exposure elevated Egr-1 and Bim expressions, and decreased Beclin-1 expression in rat cardiomyocytes. Egr-1 overexpression in IH-exposed cardiomyocytes significantly up-regulated the levels of Egr-1 and Bim, and down-regulated the level of Beclin-1. Egr-1 knockdown resulted in down-regulated expressions of Egr-1 and Bim, as well as up-regulated expression of Beclin-1. In addition, Egr-1 knockdown induced autophagy was suppressed by 3-MA treatments. TEM and autophagic flux experiments also confirmed that Egr-1 inhibited autophagy progression in IH-exposed cardiomyocytes. Egr-1 suppression protected cardiomyocytes from IH-induced injury, as evidenced by the positive correlations between Egr-1 expression and LDH leakage or apoptosis index in IH-exposed cardiomyocytes. CONCLUSIONS: IH-induced cardiomyocyte autophagy and apoptosis are regulated by the Egr-1/Bim/Beclin-1 pathway, which is a potential target for treating cardiomyocyte injury caused by MVO in the IH environment.

Are Everolimus-Eluting Stents Associated With Better Clinical Outcomes Compared to Other Drug-Eluting Stents in Patients With Type 2 Diabetes Mellitus?: A Systematic Review and Meta-Analysis.

Controversies still exist with the use of Everolimus-Eluting Stents (EES) compared to other Drug-Eluting Stents (DES) in patients with Type 2 Diabetes Mellitus (T2DM). Therefore, in order to solve this issue, we aim to compare the 1-year adverse clinical outcomes between EES and non-EE DES with a larger number of patients with T2DM.Medline, EMBASE, PubMed databases, as well as the Cochrane library were searched for randomized controlled trials (RCTs) and observational studies (OS) comparing EES and non-EE DES in patients with T2DM. One-year adverse outcomes were considered as the clinical endpoints in this study. Odd ratios (OR) with 95% confidence interval (CI) were used to express the pooled effect on discontinuous variables and the pooled analyses were performed with RevMan 5.3.Ten studies consisting of a total of 11,981 patients with T2DM (6800 patients in the EES group and 5181 in the non-EE DES group) were included in this meta-analysis. EES were associated with a significantly lower major adverse cardiac events (MACEs) with OR: 0.83, 95% CI: 0.70-0.98, P = 0.03. Revascularization including target vessel revascularization (TVR) and target lesion revascularization (TLR) were also significantly lower in the EES group with OR: 0.62, 95% CI: 0.40-0.94, P = 0.03 and OR: 0.74, 95% CI: 0.57-0.95, P = 0.02, respectively. Also, a significantly lower rate of stent thrombosis with OR: 0.63, 95% CI: 0.46-0.86, P = 0.003 was observed in the EES group. However, a similar mortality rate was reported between the EES and non-EE DES groups.During this 1-year follow-up period, EES were associated with significantly better clinical outcomes compared to non-EE DES in patients suffering from T2DM. However, further research comparing EES with non-EE DES in insulin-treated and noninsulin-treated patients with T2DM are recommended.

Comparing the Clinical Outcomes between Drug Eluting Stents and Bare Metal Stents in Patients with Insulin-Treated Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of 10 Randomized Controlled Trials.

BACKGROUND: Several studies have shown Drug Eluting Stents (DES) to be better compared to Bare Metal Stents (BMS) in patients with type 2 Diabetes Mellitus (T2DM). Since, the adverse clinical outcomes in patients with Insulin-Treated Type 2 Diabetes Mellitus (ITDM) implanted with DES and BMS have not been previously studied, we aim to compare the clinical outcomes in similar patients with cardiovascular diseases, treated with DES and BMS. METHODS: Randomized Controlled Trials (RCTs) comparing patients treated with DES and BMS were searched from PubMed and EMBASE databases. Outcome data for the patients with ITDM were carefully extracted. Major Adverse Cardiac Events (MACEs), mortality, Target Vessel Revascularization (TVR), Target Lesion Revascularization (TLR), Myocardial Infarction (MI) and Stent Thrombosis (ST) were considered as the clinical endpoints for this analysis. Odds ratios (OR) with 95% confidence intervals (CIs) were calculated and the pooled analyses were performed with RevMan 5.3 software. RESULTS: Ten RCTs consisting of 830 patients with ITDM (477 patients in the DES group and 353 patients in the BMS group) from a total number of 9,141 patients were included in this analysis. During a follow-up period from one month to one year, MACEs were not increased with the use of DES in these patients with ITDM. At 9 months, MACEs were significantly lower in the DES group with OR: 0.40, 95% CI: 0.23-0.72; P = 0.002 with no increase in mortality. TVR and TLR also favored the DES group with OR: 0.44, 95% CI: 0.22-0.88, P = 0.02 and OR: 0.28, 95% CI: 0.14-0.53; P = 0.0001 respectively at 9 months, and OR: 0.46, 95% CI: 0.23-0.94, P = 0.03 and OR: 0.28, 95% CI: 0.14-0.55; P = 0.0003 respectively at one year. Results for MI, and ST were not statistically significant. CONCLUSION: Compared to BMS, DES were associated with a significantly lower rate of repeated revascularization, without any increase in MACEs or mortality in these patients with ITDM during a follow up period of one year. However, due to the very small population size, further studies with a larger number of randomized patients are required to completely solve this issue.

Impact of Antiphospholipid Syndrome and/or Systemic Lupus Erythematosus on the Long-term Adverse Cardiovascular Outcomes in Patients After Percutaneous Coronary Intervention: A Systematic Review and Meta-analysis.

Antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) are 2 rare autoimmune disorders which commonly affect women. Several previous studies showed APS to have been evolved from SLE. Secondary APS often coexists with SLE. One common feature relating these 2 diseases are the antiphospholipid antibodies, which are found in most of the patients with APS and in approximately 30% to 40% of patients with SLE, among which, about 10% develop APS. The leading cause of death in these patients is from cardiovascular disease due to accelerated atherosclerosis, which often progresses more rapidly, compared with the general population. However, the impact of APS and/or SLE on the cardiovascular outcomes in patients undergoing percutaneous coronary intervention (PCI) is controversial. Therefore, to solve this issue, we aim to compare the long-term (≥1 year) adverse cardiovascular outcomes after PCI, in patients with APS and/or SLE, and those without these disorders.Medline and EMBASE databases were searched for studies comparing the long-term adverse cardiovascular outcomes between SLE and non-SLE, APS and non-APS, or SLE + APS and non-SLE + non-APS after PCI. We calculated odd ratios (OR) and 95% confidence intervals (CIs) for these categorical variables, and the pooled analyses were performed with RevMan 5.3.Seven studies consisting of a total of 253,436 patients (568 patients in the experimental group and 252,868 patients in the control group) were included in this meta-analysis. During a follow-up period of ≥1 year, mortality and myocardial Infarction (MI) were significantly higher in the experimental group (OR 2.02, 95% CI 1.63-2.49, P < 0.00001 and OR 1.59, 95% CI 1.23-2.05, P = 0.0004, respectively). Major adverse cardiac events and repeated revascularization were also significantly higher in the SLE/APS group (OR 2.40, 95% CI 1.42-4.03, P = 0.001 and OR 2.59, 95% CI 1.26-5.31, P = 0.01, respectively).Antiphospholipid syndrome and SLE are associated with significantly higher long-term (≥1 year) adverse cardiovascular outcomes after PCI. However, because of the limited number of patients and researches done, and due to a larger percentage of heterogeneity observed among several subgroups, this analysis may not generate a powerful result.