Cardiovascular Therapeutics

Substantial evidence suggests that the interventions of NF-κB would likely effectively prevent inflammatory response and reduce myocardial damage in the ischemic myocardium. And the NF-кB decoy ODN is a specific inhibitor that suppresses the expression of NF-κB. Herein, we revealed the effect and possible mechanism of mAb2G4/ODN/lip on myocardial ischemia-reperfusion injury (MI/RI). As shown in the results, post-treatment with mAb2G4/ODN/lip improved the impaired histological morphology in the MI/RI model and elevated cell viability in the H/R model. The mAb2G4/ODN/lip complex inhibited the NLRP3 signaling pathway and decreased the expression of LDH, IL-1β, TNF-α, IL-6, and MDA. Mechanistically, we demonstrated that post-treatment with mAb2G4/ODN/lip exerted protective effects against I/R injuries by inhibiting the NF-кB-related inflammatory response. In summary, the present study may offer a novel therapeutic strategy for treating MI/RI.

Background. Whether statins can reduce major cardiovascular adverse events (MACE) in patients with coronary artery spasm (CAS) is controversial. And most of the relevant research to date has been conducted in Asia. Methods. We systematically searched electronic databases for studies on the effect of statins on MACE in patients with CAS in Asia and published up to September 2022. We included data on MACE in a statin therapy patient group and a no-statin therapy control group. We then evaluated the effect of statin therapy on MACE in patients with CAS in Asia by meta-analysis and trial sequential analysis (TSA). All statistical analyses were performed using Stata 16.0 software and TSA software. Results. A total of 10 studies ( patients) were included in the final analysis. Meta-analysis showed that the use of statins had a significant effect on MACE in CAS patients (with RR, 0.70; 95% CI, 0.49-0.99), and the sensitivity analysis further confirmed this finding. Subgroup analysis suggested that the correlation between statin therapy and reduced MACE endpoint was stronger in Japanese patients and patients followed up for more than 4 years. But our TSA results indicated that the available samples were insufficient and further research is needed. Conclusions. Our meta-analysis suggests that statin therapy can reduce MACE in patients with CAS in Asia, and the correlation between the two was stronger in Japanese patients and patients followed up for more than 4 years.

Background. Acupuncture is widely used in the clinical treatment of essential hypertension (EH). This overview is aimed at summarizing current systematic reviews of acupuncture for EH and assessing the methodological bias and quality of evidence. Methods. Two researchers searched and extracted 7 databases for systematic reviews (SRs)/meta-analyses (MAs) and independently assessed the methodological quality, risk of bias, reporting quality, and quality of evidence of randomized controlled trials (RCTs) included in the SRs/MAs. Tools used included the measurement tool to assess systematic reviews 2 (AMSTAR-2), the risk of bias in systematic (ROBIS) scale, the checklist of preferred reporting items for systematic reviews and meta-analyses (PRISMA), and the grading of recommendations assessment, development, and evaluation (GRADE) system. Results. This overview included 14 SRs/MAs that use quantitative calculations to comprehensively assess the various effects of acupuncture in essential hypertension interventions. The methodological quality, reporting quality, risk of bias, and quality of evidence for outcome measures of SRs/MAs were all unsatisfactory. According to the results of the AMSTAR-2 assessment, all SRs/MAs were of low or very low quality. According to the results of the ROBIS evaluation, a few SRs/MAs were assessed as low risk of bias. According to the results of the PRISMA checklist assessment, SRs/MAs that were not fully reported on the checklist accounted for the majority. According to the GRADE system, 86 outcomes were assessed under different interventions in SRs/MAs, and 2 were rated as moderate-quality evidence, 23 as low-quality evidence, and 61 as very low-quality evidence. Limitations of the included SRs/MAs included the lack of necessary items, such as not being registered in the protocol, not providing a list of excluded studies, and not analyzing and addressing the risk of bias. Conclusion. Currently, acupuncture may be an effective and safe treatment for EH, but the quality of evidence is low, and caution should be exercised when applying this evidence in clinical practice.

Purpose. The aim of this study was to investigate the role of the medium-conductance calcium-activated potassium channel (KCNN4, KCa3.1) in the secretion of proinflammatory exosomes by atrial myocytes. Methods. Eighteen beagles were randomly divided into the sham group (), pacing group (), and pacing+TRAM-34 group (). Electrophysiological data, such as the effective refractory period, atrial fibrillation (AF) induction, and AF duration, were collected by programmed stimulation. Atrial tissues were subjected to hematoxylin and eosin, Masson’s trichrome, and immunofluorescence staining. The expression of KCa3.1 and Rab27a was assessed by immunohistochemistry and western blotting. The downstream signaling pathways involved in KCa3.1 were examined by rapid pacing or overexpressing KCNN4 in HL-1 cells. Results. Atrial rapid pacing significantly induced electrical remodeling, inflammation, fibrosis, and exosome secretion in the canine atrium, while TRAM-34 (KCa3.1 blocker) inhibited these changes. Compared with those in control HL-1 cells, the levels of exosome markers and inflammatory factors were increased in pacing HL-1 cells. Furthermore, the levels of CD68 and iNOS in macrophages incubated with exosomes derived from HL-1 cells were higher in the pacing-exo group than in the control group. More importantly, KCa3.1 regulated exosome secretion through the AKT/Rab27a signaling pathway. Similarly, inhibiting the downstream signaling pathway of KCa3.1 significantly inhibited exosome secretion. Conclusions. KCa3.1 promotes proinflammatory exosome secretion through the AKT/Rab27a signaling pathway. Inhibiting the KCa3.1/AKT/Rab27a signaling pathway reduces myocardial tissue structural remodeling in AF.

Mounting evidence has confirmed that essential hypertension (EH) is closely related to low-grade inflammation, but there is still a lack of in-depth understanding of the state of immune cells in the circulating blood of patients with EH. We analyzed whether hypertensive peripheral blood immune cell balance was destroyed. The peripheral blood mononuclear cells (PBMCs) of all subjects were analyzed using time-of-flight cytometry (CyTOF) based on 42 kinds of metal-binding antibodies. CD45⁺ cells were categorized into 32 kinds of subsets. Compared with the health control (HC) group, the percentage of total dendritic cells, two kinds of myeloid dendritic cell subsets, one intermediate/nonclassical monocyte subset and one CD4⁺ central memory T cell subset in the EH group, was significantly higher; the percentage of low-density neutrophils, four kinds of classical monocyte subsets, one CD14^lowCD16^- monocyte subset, one naive CD4⁺ and one naive CD8⁺ T cell subsets, one CD4⁺ effector and one CD4⁺ central memory T cell subsets, one CD8⁺ effector memory T cell subset, and one terminally differentiated γδ T cell subset, decreased significantly in EH. What is more, the expression of many important antigens was enhanced in CD45⁺ immune cells, granulocytes, and B cells in patients with EH. In conclusion, the altered number and antigen expression of immune cells reflect the imbalanced immune state of the peripheral blood in patients with EH.

Background. Doxorubicin-induced cardiotoxicity has been closely concerned in clinical practice. Rev-erbα is a transcriptional repressor that emerges as a drug target for heart diseases recently. This study is aimed at investigating the role and mechanism of Rev-erbα in doxorubicin-induced cardiotoxicity. Methods. H9c2 cells were treated with 1.5 μM doxorubicin, and C57BL/6 mice were treated with a 20 mg/kg cumulative dose of doxorubicin to construct doxorubicin-induced cardiotoxicity models in vitro and in vivo. Agonist SR9009 was used to activate Rev-erbα. PGC-1α expression level was downregulated by specific siRNA in H9c2 cells. Cell apoptosis, cardiomyocyte morphology, mitochondrial function, oxidative stress, and signaling pathways were measured. Results. SR9009 alleviated doxorubicin-induced cell apoptosis, morphological disorder, mitochondrial dysfunction, and oxidative stress in H9c2 cells and C57BL/6 mice. Meanwhile, PGC-1α and downstream signaling NRF1, TAFM, and UCP2 expression levels were preserved by SR9009 in doxorubicin-treated cardiomyocytes in vitro and in vivo. When downregulating PGC-1α expression level by specific siRNA, the protective role of SR9009 in doxorubicin-treated cardiomyocytes was attenuated with increased cell apoptosis, mitochondrial dysfunction, and oxidative stress. Conclusion. Pharmacological activation of Rev-erbα by SR9009 could attenuate doxorubicin-induced cardiotoxicity through preservation of mitochondrial function and alleviation of apoptosis and oxidative stress. The mechanism is associated with the activation of PGC-1α signaling pathways, suggesting that PGC-1α signaling is a mechanism for the protective effect of Rev-erbα against doxorubicin-induced cardiotoxicity.