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Background Myocardial reperfusion injury is often accompanied by cell death and inflammatory reactions. Recently, pyroptosis is gradually recognized as pivotal role in cardiovascular disease. However, little is known about the regulatory role of beclin1 in the control of caspase-4 activation and pyroptosis. The present study confirmed whether beclin1 regulates caspase-4 mediated pyroptosis and thereby protects Human Cardiac microvascular endothelial cells (HCMECs) against injury. Methods TTC and Evan's blue dye, western blot, immunofluorescence and immunohistochemistry staining were performed in wild mice and transgenic mice with overexpression of beclin 1(BECN1-Tg). CMECs were transfected with a beclin1 lentivirus. The cell cytotoxicity was analyzed by LDH-Cytotoxicity Assay Kit. The protein levels of autophagy protein (Beclin1, p62 and LC3II/LC3I) and caspase-4/GSDMD pathway were determined by western blot. Autophagic vacuoles in cells were monitored with RFP-GFP-LC3 using fluorescence microscope. Results I/R caused caspase-4 activity and gasdermin D expression increase in vivo and in vitro. Overexpression of beclin1 in heart tissue and CMECs suppressed the caspase-4 activity and decreased the levels of gasdermin D; meanwhile beclin1 overexpression also reduced IL-1β levels, promoted autophagy (p62 expression was inhibited while LC3II expression was increased) in the heart and CMECs. Interestingly, beclin1 overexpression increased animal survival and attenuated myocardial infarct size (45 ± 6.13 vs 22 ± 4.37), no-reflow area (39 ± 5.22 vs 16 ± 2.54) post-myocardial ischemia reperfusion. Conclusions Induction of beclin-1 signaling can be a potential therapeutic target in myocardial reperfusion-induced microvascular injury.

BackgroundPatients with acute myocardial infarction (AMI) and bundle-branch block have poor prognoses. The new European Society of Cardiology guideline suggests a primary percutaneous coronary intervention strategy when persistent ischemic symptoms occur in patients with persistent ischemic symptoms and right bundle-branch block (RBBB), but the level of evidence is not high. In fact, the presence of RBBB may lead to the misdiagnosis of transmural ischemia and mask the early diagnosis of ST-elevation myocardial infarction. Moreover, new-onset RBBB is occasionally caused by AMI. Our study aims to investigate the prognostic value of new-onset RBBB in AMI.Methods and ResultsWe conducted a meta-analysis of studies to evaluate the prognostic value of RBBB in AMI patients. Of 914 primary records, five studies and 874 MI patients were included for meta-analysis. Compared with previous RBBB, AMI patients with new-onset RBBB had a higher risk of long-term mortality (RR, 1.66, 95% CI [1.31–2.09], I2 = 0.0%, p = 0.000, n = 2), ventricular arrhythmia (RR, 4.86, 95% CI [2.10–11.27], I2 = 0.0%, p = 0.000, n = 3), and cardiogenic shock (RR, 2.76, 95% CI [1.66–4.59], I2 = 0.0%, p = 0.000, n = 3), but a lower risk of heart failure (RR, 0.66, 95% CI [0.52–0.85], I2 = 2.50%, p = 0.001, n = 4). Compared with AMI patients with new-onset permanent RBBB, patients with new-onset transient RBBB had a lower risk of short-term mortality (RR, 0.20, 95% CI [0.11–0.37], I2 = 44.1%, p = 0.000, n = 4).ConclusionNew-onset RBBB is likely to increase long-term mortality, ventricular arrhythmia, and cardiogenic shock, but not heart failure in AMI patients. AMI patients with new-onset transient RBBB have a lower risk of short-term mortality than those with new-onset permanent RBBB. Revascularization therapies should be considered when persistent ischemic symptoms occur in patients with RBBB, especially new-onset RBBB.

Previous studies have demonstrated that the aberrant expression of Wnt5a occurs in atherosclerotic lesions. However, the precise role of Wnt5a in the pathogenesis of atherosclerosis remains largely unknown. The present study was undertaken to determine whether the RNA interference of Wnt5a in vivo by adenovirus (Ad)-mediated small interfering RNA (siRNA) transfection is capable of inhibiting the progression of atherosclerosis. Recombinant adenovirus carrying siRNA targeting Wnt5a (Ad-Wnt5a siRNA) was designed. Male apolipoprotein E-deficient (ApoE(-/-)) mice were fed a high-fat diet to induce the pathogenesis of atherosclerosis. Mice were randomly divided into 3 groups (n=15 in each group): the mock group, which received treatment with phosphate-buffered saline (PBS); the Ad-NC group, which received treatment with Ad-non-specific siRNA; and the Ad-Wnt5a siRNA group, which received treatment with Ad-Wnt5a siRNA. Treatment with Ad-Wnt5a siRNA markedly inhibited the mRNA and protein expression of Wnt5a in the aortic tissues. The knockdown of Wnt5a had no significant effect on blood lipid levels, but it suppressed atherosclerotic development and increased plaque stability, which was determined by hematoxylin and eosin staining, picrosirius red staining and Oil Red O staining. Furthermore, the mRNA and protein expression of inflammatory cytokines, including monocyte chemotactic protein-1 (MCP-1), cyclooxygenase-2 (COX-2), matrix metalloproteinase (MMP)-2 and MMP-9 was significantly downregulated in the Ad-Wnt5a siRNA group. In addition, the knockdown of Wnt5a inhibited the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. These results demonstrate that Ad-mediated Wnt5a silencing in vivo attenuates the development of atherosclerotic disease by reducing inflammatory mediators involved in the MAPK/NF-κB pathways.

Abstract. The value of the right bundle branch block (RBBB) in the treatment of acute myocardial infarction remains unclear. Studies on the RBBB may significantly influence the treatment of acute myocardial infarction. A total of 845 patients with acute myocardial infarction who underwent primary coronary angiography at Henan Provincial People's Hospital were analyzed. Higher peak enzyme levels, a higher ratio of Killip ≥II and closer proximal occlusion of infarct-related artery (IRA) were observed in patients with RBBB compared with those without. The ratio of TIMI flow 0/1 of IRA and ratio of received primary percutaneous coronary intervention (PCI) to IRA in the RBBB group were significantly higher compared with those in the left (L) BBB or no BBB groups. The in-hospital major adverse cardiac events (MACE) incidence in the RBBB group was higher compared with that in the no BBB group, but there was no significant difference between the RBBB and LBBB groups. Logistic regression revealed that proximal occlusion and TIMI flow 0/1 of IRA were predictive factors of RBBB. Cox regression analysis identified RBBB [risk ratio (RR), 4.682; P<0.001] and LBBB (RR, 3.687; P<0.001) as independent predictors of in-hospital MACE. The cumulative one-year survival rate in the RBBB group was significantly lower than those in the no BBB group (P<0.05) and the LBBB group (P<0.05). Similar to the guidelines regarding new onset of LBBB, new onset RBBB should be considered as a standard indicator for reperfusion therapy; as RBBB is associated with more severe symptoms, and higher incidents of complete occlusion of IRA and primary PCI treatment compared with LBBB.