Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification.

BACKGROUND: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell-specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing ß-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell-specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE-induced upregulation of Runx2. CONCLUSIONS: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.

Posttranslational modifications of platelet adhesion receptors.

Platelets play a key role in normal hemostasis, whereas pathological platelet adhesion is involved in various cardiovascular events. The underlying cause in cardiovascular events involves plaque rupture leading to subsequent platelet adhesion, activation, release, and eventual thrombosis. Traditional antithrombotic drugs often target the signal transduction process of platelet adhesion receptors by influencing the synthesis of some key molecules, and their effects are limited. Posttranslational modifications (PTMs) of platelet adhesion receptors increase the functional diversity of the receptors and affect platelet physiological and pathological processes. Antithrombotic drugs targeting PTMs of platelet adhesion receptors may represent a new therapeutic idea. In this review, various PTMs, including phosphorylation, glycosylation, ubiquitination, nitrosylation, methylation, lipidation, and proteolysis, of three platelet adhesion receptors, glycoprotein Ib-IX-V (GPIb-IX-V), glycoprotein VI (GPVI), and integrin αIIbß3, are reviewed. It is important to comprehensively understand the PTMs process of platelet adhesion receptors.

Short-term efficacy of angiotensin receptor-neprilysin inhibitor treatment in patients with ST-segment elevation myocardial infarction with reduced ejection fraction after primary percutaneous coronary intervention: a propensity score matching study.

BACKGROUND: Acute myocardial infarction (AMI) causes a series of pathophysiological changes, including myocardial necrosis, myocardial edema, and microvascular damage. These changes eventually lead to severe cardiovascular events, such as ventricular remodeling, heart failure, and papillary dysfunction. Impaired cardiac function after ST-segment elevation myocardial infarction (STEMI) often manifests as a decrease in left ventricular ejection fraction (LVEF). Clinical trials have shown that angiotensin receptor-neprilysin inhibitor (ARNI) treatment has the potential to improve LVEF in patients with STEMI after primary percutaneous coronary intervention (PPCI). OBJECTIVE: The purpose of this study was to evaluate the short-term efficacy of ARNI versus angiotensin-converting enzyme inhibitor (ACEI) treatment in patients with STEMI who exhibit reduced LVEF after PPCI. METHODS: A total of 169 patients with STEMI exhibiting post-PPCI LVEF below 50% who were orally treated with ARNI between December 2017 and August 2020 were selected as the experimental group. A total of 136 patients with STEMI exhibiting post-PPCI LVEF below 50% who were orally treated with an ACEI between January 2016 and August 2020 were selected as the control group. LVEF was measured using cardiac ultrasonography during hospitalization and 3 months after discharge. Linear and logistic regression analyses were performed to compare patient demographics and hospitalization variables to evaluate the risk factors for change and rate of improvement in LVEF. Propensity score matching (PSM) was used to account for confounding factors. RESULTS: After PSM, the study cohort consisted of 81 patients in the ARNI group and 123 in the ACEI group. After an average follow-up period of 3 months, no significant difference was noted in the LVEF improvement rate between the experimental and control groups (P = 0.475, 95% CI: -0.062 to 0.134). Multivariate logistic regression analysis also indicated no significant correlation between the change in LVEF and oral ARNI treatment in patients with STEMI exhibiting reduced LVEF after PPCI (P > 0.05). CONCLUSION: The short-term effect of ARNI treatment on the cardiac function of patients with STEMI and reduced LVEF after PPCI is not superior to that of ACEI treatment.

Mortality in cardiogenic shock patients receiving mechanical circulatory support: a network meta-analysis.

OBJECTIVE: Mechanical circulatory support (MCS) devices are widely used for cardiogenic shock (CS). This network meta-analysis aims to evaluate which MCS strategy offers advantages. METHODS: A systemic search of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials was performed. Studies included double-blind, randomized controlled, and observational trials, with 30-day follow-ups. Paired independent researchers conducted the screening, data extraction, quality assessment, and consistency and heterogeneity assessment. RESULTS: We included 39 studies (1 report). No significant difference in 30-day mortality was noted between venoarterial extracorporeal membrane oxygenation (VA-ECMO) and VA-ECMO plus Impella, Impella, and medical therapy. According to the surface under the cumulative ranking curve, the optimal ranking of the interventions was surgical venting plus VA-ECMO, medical therapy, VA-ECMO plus Impella, intra-aortic balloon pump (IABP), Impella, Tandem Heart, VA-ECMO, and Impella plus IABP. Regarding in-hospital mortality and 30-day mortality, the forest plot showed low heterogeneity. The results of the node-splitting approach showed that direct and indirect comparisons had a relatively high consistency. CONCLUSIONS: IABP more effectively reduce the incidence of 30-day mortality compared with VA-ECMO and Impella for the treatment of CS.

Inhibition of adenosine kinase attenuates myocardial ischaemia/reperfusion injury.

Increased adenosine helps limit infarct size in ischaemia/reperfusion-injured hearts. In cardiomyocytes, 90% of adenosine is catalysed by adenosine kinase (ADK) and ADK inhibition leads to higher concentrations of both intracellular adenosine and extracellular adenosine. However, the role of ADK inhibition in myocardial ischaemia/reperfusion (I/R) injury remains less obvious. We explored the role of ADK inhibition in myocardial I/R injury using mouse left anterior ligation model. To inhibit ADK, the inhibitor ABT-702 was intraperitoneally injected or AAV9 (adeno-associated virus)-ADK-shRNA was introduced via tail vein injection. H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to elucidate the underlying mechanisms. ADK was transiently increased after myocardial I/R injury. Pharmacological or genetic ADK inhibition reduced infarct size, improved cardiac function and prevented cell apoptosis and necroptosis in I/R-injured mouse hearts. In vitro, ADK inhibition also prevented cell apoptosis and cell necroptosis in H/R-treated H9c2 cells. Cleaved caspase-9, cleaved caspase-8, cleaved caspase-3, MLKL and the phosphorylation of MLKL and CaMKII were decreased by ADK inhibition in reperfusion-injured cardiomyocytes. X-linked inhibitor of apoptosis protein (XIAP), which is phosphorylated and stabilized via the adenosine receptors A2B and A1/Akt pathways, should play a central role in the effects of ADK inhibition on cell apoptosis and necroptosis. These data suggest that ADK plays an important role in myocardial I/R injury by regulating cell apoptosis and necroptosis.

Short- and Long-Term Prognosis of Intravascular Ultrasound-Versus Angiography-Guided Percutaneous Coronary Intervention: A Meta-Analysis Involving 24,783 Patients.

BACKGROUND: Intravascular ultrasound (IVUS) guided percutaneous coronary intervention (PCI) has potential benefits. This meta-analysis aimed to explore whether IVUS-guided PCI had better short- and long-term prognoses than angiography-guided PCI. METHODS: We retrieved studies from PubMed, Embase, and Cochrane Library. Clinical trials including retrospective and randomized controlled trials (RCTs) that compared IVUS-guided PCI with angiography-guided PCI were included. The patients were followed up after operation at 30 days, 1 year, 2 years, and 3 years. The clinical outcomes were target lesion revascularization (TLR), target vessel revascularization (TVR), and MACEs, including stent thrombosis (ST), myocardial infarction (MI), cardiac death, and all-cause death. The study population included patients with MI, coronary bifurcation lesions, short or long lesions, and unprotected left main coronary artery stenosis (ULMCA). The quality of retrospective trials was evaluated using the Newcastle-Ottawa Scale, and the quality of randomized controlled trials was evaluated using the Jadad score. A total of 20 clinical trials met the criteria. Three trials were randomized controlled trials, while 17 were retrospective trials. RESULTS: A total of 24,783 patients were included. In observational trials, the OR of MACEs was 0.49 (95% CI: 0.38-0.62) in 30 days, 0.65 (95% CI: 0.58-0.73) in one year, 0.51 (95% CI: 0.36-0.71) in two years, and 0.45 (95% CI: 0.31-0.65) in three years. In patients with long coronary lesions, the OR of MACEs in 1 year was 0.64 (95% CI: 0.28-1.50). In patients with left main artery disease, the OR of MACEs in 3 years was 0.42 (95% CI: 0.26-0.67). Compared with angiography-guided PCI, IVUS-guided PCI was associated with a lower incidence of MACEs during the same following period. CONCLUSION: Compared with angiography-guided PCI, IVUS-guided PCI has better performance in reducing the occurrence of MACEs.

Oppositely Charged Pickering Emulsion Co-Stabilized by Chitin Nanoparticles and Fucoidan: Influence of Environmental Stresses on Stability and Antioxidant Activity.

Single emulsifiers exhibit varying degrees of restriction in stabilizing emulsions. Oppositely charged chitin nanoparticles and fucoidan complex particles were used as emulsifiers to stabilize a o/w Pickering emulsion and explore its stability and antioxidant activity under different environmental stresses. The results showed that the emulsion with the smallest mean particle size (1.02 µm) and strongest zeta potential (-29.3 mV) was formed at pH 7. Moreover, at this pH, it presented the highest physical stability and antioxidant activity and the lowest emulsion creaming index. The investigation of the effect of temperature on the stability and antioxidant activity of the emulsion revealed that, after freezing/thawing at -20 °C, the emulsion was unstable, the particle size increased, and the stability and antioxidant activity were low. In contrast, the emulsions treated at 25, 37, and 60 °C displayed no significant differences and exhibited high stabilities and antioxidant activities. Additionally, increasing the salt ion concentration further decreased the emulsion stability and antioxidant activity. Particularly, the emulsion with a salt concentration of 500 mM displayed the lowest stability, and stratification occurred after 30 d of storage. The Pickering emulsion remained stable under different environmental stresses expect for at a temperature of -20 °C and 500 mM salt ion concentration.

Timing of angiography and outcomes in patients with non-ST-segment elevation myocardial infarction: Insights from the evaluation and management of patients with acute chest pain in China registry.

Objective: Although an invasive strategy has been recommended within 24 h for patients with non-ST-segment elevation myocardial infarction (NSTEMI), the optimal timing of the invasive strategy remains controversial. We sought to investigate the association between the different timings of invasive strategies and clinical outcomes in patients with NSTEMI. Materials and methods: Patients admitted with NSTEMI from the Evaluation and Management of Patients with Acute ChesT pain in China (EMPACT) registry between January 2016 and September 2017 were included. The primary outcomes were major adverse cardiac events (MACEs) within 30 days. Multivariable logistic regression was performed to assess independent risk factors for MACEs. Results: A total of 969 patients with NSTEMI from the EMPACT Registry were eligible for this study. Coronary angiography (CAG) was performed in 501 patients [<24 h, n = 150 (15.5%); ≥ 24 h, n = 351 (36.2%)]. The rate of MACEs at 30 days in all patients was 9.2%, including 54 (5.6%) deaths. Patients who underwent CAG had a lower rate of MACEs and mortality than those who did not receive CAG (MACEs: 5.6% vs. 13.0%, P < 0.001; mortality: 1.6% vs. 9.8%, P < 0.001). Nonetheless, no statistically significant difference was found in the rates of MACEs and mortality between the early (< 24 h) and delayed (≥ 24 h) CAG groups. Older age (OR: 1.036, 95% CI: 1.007, 1.065, P = 0.014), and acute heart failure (OR: 2.431, 95% CI: 1.244, 4.749, P = 0.009) increased the risk of MACEs and protective factors were underwent CAG (OR: 0.427, 95% CI: 0.219, 0.832, P = 0.012) or PCI (OR: 0.376, 95% CI: 0.163, 0.868, P = 0.022). In the multilevel logistic regression, older age (OR: 0.944, 95% CI: 0.932, 0.957, P < 0.001), cardiogenic shock (OR: 0.233, 95% CI: 0.079, 0.629, P = 0.009), pulmonary moist rales (OR: 0.368, 95% CI: 0.197, 0.686, P = 0.002), and prior chronic kidney disease (OR: 0.070, 95% CI: 0.018, 0.273, P < 0.001) was negatively associated with CAG. Conclusion: This real-world cohort study of NSTEMI patients confirmed that the early invasive strategy did not reduce the incidence of MACEs and mortality within 30 days compared with the delayed invasive strategy in NSTEMI patients.

Clinical Outcomes Following Simple or Complex Stenting for Coronary Bifurcation Lesions: A Meta-Analysis.

Background: Stent placement remains a challenge for coronary bifurcation lesions. While both simple and complex stenting strategies are available, it is unclear which one results in better clinical outcomes. This meta-analysis aims to explore the long-term prognosis following treatment with the 2 stenting strategies. Method: Randomized controlled trials found from searches of the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were included in this meta-analysis. The complex stent placement strategy was identified as the control group, and the simple stent placement strategy was identified as the experimental group. Data were synthesized with a random effects model. The quality of the randomized controlled trials was assessed by Jadad scale scores. The clinical endpoints at 6 months, 1 year, and 5 years were analyzed. Results: A total of 11 randomized controlled trials met the inclusion criteria. A total of 2494 patients were included in this meta-analysis. The odds ratio [OR] of the major adverse cardiac events (MACEs) at 6 months was 0.85 (95% confidence interval [CI] 0.53-1.35; P = .49, I 2 = 0%). The OR of the MACEs at 1 year was 0.61 (95% CI 0.36-1.05; P = .08, I 2 = 0%). The OR of the MACEs at 5 years was 0.69 (95% CI 0.51-0.92; P = .01, I 2 = 0%). Compared with the complex strategy, the simple strategy was associated with a lower incidence of MACEs at 5 years. Conclusion: Compared to the complex stenting strategy, the simple stenting strategy can better reduce the occurrence of long-term MACEs for coronary bifurcation lesions.

Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis.

Background: Inflammatory disorder and acinar cell death contribute to the initiation and progression of severe acute pancreatitis (SAP). Adenosine kinase (ADK) has potential effects on both inflammation and cell death. However, the role of ADK in SAP remains to be explored. Methods: To establish an experimental SAP model, male C57BL/6 mice were intraperitoneally injected with cerulein (50 µg/kg, seven doses at hourly intervals) and LPS (10 mg/kg, at the last cerulein injection). For ADK inhibition, ABT702 (1.5 mg/kg) was intraperitoneally injected 1 h before cerulein treatment. The pancreas and serum were collected and analyzed to determine the severity of pancreatic injury and explore the potential pathophysiological mechanisms. Pancreatic acinar cells (AR42J) were used to explore the in vitro effects of ADK inhibition on cerulein-induced inflammation and necroptotic cell death. Results: ADK inhibition notably attenuated the severity of SAP, as indicated by the decreased serum amylase (7,416.76 ± 1,457.76 vs. 4,581.89 ± 1,175.04 U/L) and lipase (46.51 ± 11.50 vs. 32.94 ± 11.46 U/L) levels and fewer pancreatic histopathological alterations (histological scores: 6.433 ± 0.60 vs. 3.77 ± 0.70). MOMA-2 and CD11b staining confirmed that ADK inhibition prevented the infiltration of neutrophils and macrophages. The phosphorylation of nuclear factor-κB (NF-κB) was also reduced by ADK inhibition. ADK inhibition markedly limited the necrotic area of the pancreas and prevented the activation of the necroptotic signaling pathway. Endoplasmic reticulum (ER) stress was activated in the pancreas using the SAP model and cerulein-treated AR42J cells whereas ADK inhibition reversed the activation of ER stress both in vivo and in vitro. Moreover, the alleviating effects of ADK inhibition on ER stress, inflammation, and cell necroptosis were eliminated by the adenosine A2A receptor antagonist. Conclusion: ADK inhibition reduced inflammation and necroptotic acinar cell death in SAP via the adenosine A2A receptor/ER stress pathway, suggesting that ADK might be a potential therapeutic target for SAP.

4-Hydroxy-2-Nonenal Promotes Cardiomyocyte Necroptosis via Stabilizing Receptor-Interacting Serine/Threonine-Protein Kinase 1.

Background: Necroptosis is a vital regulator of myocardial ischemia/reperfusion (MI/R) injury. Meanwhile, 4-hydroxy-2-nonenal (4-HNE) is abundantly increased during MI/R injury. However, whether 4-HNE induces cardiomyocyte necroptosis during MI/R remains unknown. Methods: To observe the relationship between 4-HNE and necroptosis during MI/R, C57BL/6 mice and aldehyde dehydrogenase 2-transgenic (ALDH2-Tg) mice were both exposed to left anterior descending artery ligation surgery to establish MI/R injury models. For further study, isolated mouse hearts and H9c2 cells were both treated with 4-HNE to elucidate the underlying mechanisms. Results: Necroptosis and 4-HNE were both upregulated in I/R-injured hearts. Cardiomyocyte necroptosis was significantly decreased in I/R-injured hearts from ALDH2-Tg mice as compared with that of wild-type mice. In vitro studies showed that necroptosis was enhanced by 4-HNE perfusion in a time- and concentration-dependent manner. Knockdown of receptor-interacting serine/threonine-protein kinase 1 (RIP1) using small interfering RNA (siRNA) prevented 4-HNE-induced cardiomyocyte necroptosis, manifesting that RIP1 played a key role in the upregulation of cell necroptosis by 4-HNE. Further studies found that 4-HNE reduced the protein degradation of RIP1 by preventing K48-polyubiquitination of RIP1. Conclusion: 4-HNE contributes to cardiomyocyte necroptosis by regulating ubiquitin-mediated proteasome degradation of RIP1.

Curcumin attenuates collagen-induced rat arthritis via anti-inflammatory and apoptotic effects.

Curcumin is a natural herbal product that has been popularly used to treat autoimmune diseases in China; however, its effects on rheumatoid arthritis and its mechanism are not clear. The main purposes of this study are to explore the therapeutic effects of curcumin on collagen-induced arthritis (CIA) rats and the pharmacological mechanism. In the present study, CIA rats were established by injecting bovine type II collagen. Curcumin and methotrexate were then orally administered daily, and the swelling degree of the hind limb joints was scored every two days. Histopathological changes were observed by hematoxylin-eosin staining. The levels of cytokines (TNF-α, IL-1ß, IL-17 and TGF-ß) were detected by radioimmunoassay, while the expression of IκBα and COX-2 was detected by Western blot. In addition, cell viability was detected by CCK-8 assay, and the effect of curcumin on macrophage apoptosis was detected by flow cytometry and TUNEL assay. The results indicated that in vivo curcumin attenuated the degree of joint swelling of rats and the further development of joint histopathology. Moreover, it downregulated the levels of cytokines. In vitro curcumin inhibited the degradation of IκBα and reduced the production of COX-2 in LPS-induced inflammatory RAW264.7 cells. Importantly, curcumin significantly induced macrophage apoptosis. In conclusion, in this study, we have demonstrated that curcumin exerts therapeutic effects on arthritis in CIA rats and has a strong pharmacological activity on reducing the inflammatory response in macrophages. Its mechanism may be related to the inhibition of the NF-κB signaling pathway and the promotion of macrophage apoptosis.