Adenosine kinase promotes post-infarction cardiac repair by epigenetically maintaining reparative macrophage phenotype.

Pro-inflammatory and reparative macrophages are crucial in clearing necrotic myocardium and promoting cardiac repair after myocardial infarction (MI), respectively. Extracellular adenosine has been demonstrated to modulate macrophage polarization through adenosine receptors. However, the role of intracellular adenosine in macrophage polarization has not been explored and adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels. Here, we aimed to elucidate the role of ADK in macrophage polarization and its subsequent impact on MI. We demonstrated that ADK was upregulated in bone marrow-derived macrophages (BMDMs) after IL-4 treatment and was highly expressed in the infarct area at day 7 post-MI, especially in macrophages. Compared with wild-type mice, myeloid-specific Adk knockout mice showed increased infarct size, limited myofibroblast differentiation, reduced collagen deposition and more severe cardiac dysfunction after MI, which was related to impaired reparative macrophage phenotype in MI tissue. We found that ADK deletion or inhibition significantly decreased the expression of reparative genes, such as Arg1, Ym1, Fizz1, and Cd206 in BMDMs after IL-4 treatment. The increased intracellular adenosine due to Adk deletion inhibited transmethylation reactions and decreased the trimethylation of H3K4 in BMDMs after IL-4 treatment. Mechanistically, we demonstrated that Adk deletion suppressed reparative macrophage phenotype through decreased IRF4 expression, which resulted from reduced levels of H3K4me3 on the Irf4 promotor. Together, our study reveals that ADK exerts a protective effect against MI by promoting reparative macrophage polarization through epigenetic mechanisms.

Photothermal Nanozymatic Nanoparticles Induce Ferroptosis and Apoptosis through Tumor Microenvironment Manipulation for Cancer Therapy.

It is highly desirable to design a single modality that can simultaneously trigger apoptosis and ferroptosis to efficiently eliminate tumor progression. Herein, a nanosystem based on the intrinsic properties of tumor microenvironment (TME) is designed to achieve tumor control through the simultaneous induction of ferroptosis and apoptosis. CuCP molecules are encapsulated in a liposome-based nanosystem to assemble into biocompatible and stable CuCP nanoparticles (CuCP Lipo NPs). This nanosystem intrinsically possesses nanozymatic activity and photothermal characteristics due to the property of Cu atoms and the structure of CuCP Lipo NPs. It is demonstrated that the synergistic strategy increases the intracellular lipid-reactive oxides species, induces the occurrence of ferroptosis and apoptosis, and completely eradicates the tumors in vivo. Proteomics analysis further discloses the key involved proteins (including Tp53, HMOX1, Ptgs2, Tfrc, Slc11a2, Mgst2, Sod1, and several GST family members) and pathways (including apoptosis, ferroptosis, and ROS synthesis). Conclusively, this work develops a strategy based on one nanosystem to synergistically induce ferroptosis and apoptosis in vivo for tumor suppression, which holds great potential in the clinical translation for tumor therapy.

Effect of pharmacological treatment on outcomes of heart failure with preserved ejection fraction: an updated systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Optimal treatment strategies for patients with heart failure with preserved ejection fraction (HFpEF) remain uncertain. The goal of this study was to compare the treatment effects of different therapeutic agents for patients with HFpEF. METHODS: Randomized controlled trials (RCTs) published before June 2022 were searched from PubMed, Clinical Trials gov, and the Cochrane Central Register databases. Combined odds ratios (ORs) with 95% confidence intervals (CI) were calculated for the primary and secondary outcomes. All-cause death was the primary endpoint and cardiac death, hospitalization for HF, and worsening HF (WHF) events were secondary endpoints in this meta-analysis. RESULTS: Fifteen RCTs including 31,608 patients were included in this meta-analysis. All-cause and cardiac death were not significantly correlated between drug treatments and placebo. Compared with placebo, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor neprilysin inhibitors (ARNIs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors significantly reduced HF hospitalizations [odds ratio (OR) = 0.64, (95% confidence interval (95%CI 0.43 - 0.96), OR = 0.73, (95%CI 0.61 - 0.86), and OR = 0.74, (95%CI 0.66 - 0.83), respectively] without heterogeneity among studies. Only SGLT2 inhibitors significantly reduced WHF events [OR = 0.75, (95%CI 0.67 - 0.83)]. CONCLUSIONS: No treatments were effective in reducing mortality, but ARNIs, ACEIs or SGLT2 inhibitors reduced HF hospitalizations and only SGLT2 inhibitors reduced WHF events for patients with HFpEF.

Renal Safety and Renin-Angiotensin-Aldosterone System Inhibitors in Patients With Contrast Media Exposure: A Multicenter Randomized Controlled Study.

ABSTRACT: There is no clear consensus on the safety of renin-angiotensin-aldosterone system inhibitors in patients with contrast media exposure. We aimed to assess the safety of renin-angiotensin-aldosterone system inhibitors in patients exposed to contrast media at 1-year follow-up. Patients treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) were recruited and randomly divided into 2 groups (1:1 ratio): with ACEI/ARB group (ACEI/ARB continued throughout the study period) and without ACEI/ARB group (ACEI/ARB stopped 24 hours before and continued 48 hours after the procedure). The primary endpoint was contrast-induced acute kidney injury (CI-AKI) and secondary endpoints were major adverse cardiovascular events (MACEs), and the need for renal replacement therapy during hospitalization and at 1-year follow-up. The occurrence rates of CI-AKI were not comparable in the ACEI/ARB group and the without ACEI/ARB group (2.92% and 2.62%, respectively; P = 0.866). No significant between-group differences were found with respect to the frequency of MACEs or renal replacement therapy during hospitalization and at 1-year follow-up. On subgroup analysis, among patients with estimated glomerular filtration rate (eGFR) < 45 mL/min, the incidence of CI-AKI was significantly higher in the ACEI/ARB group [17.95% (14/78) vs. 6.02% (5/83), P = 0.029]. Among patients with eGFR ≥ 45 mL/min, the incidence of CI-AKI was comparable in the 2 groups [0.87% (5/572) vs. 2.12% (12/567), P = 0.094]. The incidence of MACEs and renal replacement therapy was not comparable in the 2 groups, during hospitalization and at 1-year follow-up. ACEI or ARB treatment can safely be continued after exposure to contrast media, but not in patients with eGFR < 45 mL/min.

Ticagrelor versus clopidogrel in reducing inflammatory cell infiltration of thrombus aspirated in patients with ST-elevation myocardial infarction.

BACKGROUND: Ticagrelor provides more rapid, potent, and consistent anti-platelet efficacy than clopidogrel. This randomized trial aimed to evaluate the anti-inflammation effects of ticagrelor versus clopidogrel on thrombus aspirated from the ST-elevation myocardial infarction (STEMI) patients. METHOD: A total of 98 patients with STEMI and intended percutaneous coronary intervention (PCI) were randomly assigned to receive clopidogrel (600-mg loading dose) or ticagrelor (180-mg loading dose), of whom 55 with large thrombus burden underwent thrombus aspiration during PCI. Thrombus specimens were successfully aspirated from 49 patients. Finally, 24 patients in the clopidogrel group and 23 in the ticagrelor group completed the study. Inflammatory cells within thrombi were assessed by hematoxylin-eosin and immunohistochemistry stainings. RESULTS: Compared with the clopidogrel group, the number of total inflammatory cells per mm2 thrombus area in the ticagrelor group was decreased by 28% (P = 0.009). The numbers of neutrophils and myeloperoxidase-positive cells per mm2 thrombus area in the ticagrelor group were respectively decreased by 35% (P = 0.016) and 28% (P = 0.047), as compared with those in the clopidogrel group. Moreover, ticagrelor treatment reduced the ratio of monocytes number higher than 250 per mm2 thrombus area compared with clopidogrel treatment (4% versus 29%, P = 0.048). CONCLUSION: In patients with undergoing PCI for STEMI, the loading dose ticagrelor regimen was associated with a reduction in inflammatory cell infiltration within thrombus compared with the loading dose clopidogrel regimen.

Intravenous morphine use in acute heart failure increases adverse outcomes: a meta-analysis.

Intravenous morphine is a controversial treatment for acute heart failure (AHF). This study aimed to evaluate and compare the efficacy of intravenous morphine treatment vs. no morphine treatment in AHF patients. Relevant research conducted before June 2020 was retrieved from electronic databases. One unpublished study of our own was also included. Studies were eligible for inclusion if they compared AHF patients treated with intravenous morphine and patients who did not receive morphine. This meta-analysis included three propensity-matched cohorts and two retrospective analyses, involving a total of 149,967 patients (intravenous-morphine group, n = 22,072; no-morphine group, n = 127,895). There was a non-significant increase in the in-hospital mortality in the morphine group (combined odds ratio [OR] = 2.14, 95% confidence interval [CI]: 0.88-5.23, p = 0.095, I2 = 97.1%). However, subgroup analyse showed that the rate of in-hospital mortality with odds of 1.41 times more likely (95% CI: 1.11-1.80, p = 0.005, I2 = 0%) in those receiving vs. not receiving intravenous morphine. No significant correlation was found between intravenous morphine and invasive mechanical ventilation (OR = 2.19, 95% CI: 0.84-5.73, p = 0.10, I2 = 94.2%; subgroup analysis: OR = 2.24, 95% CI: 0.70-7.21, p = 0.176, I2 = 95.1%) or long-term mortality (hazard ratio = 1.15, 95% CI: 0.96-1.34, p = 0.335; I2 = 8.6%). The administration of intravenous morphine to patients with AHF may be related to in-hospital mortality, but not to invasive mechanical ventilation and long-term mortality.

Validity of SOFA score as a prognostic tool for critically ill elderly patients with acute infective endocarditis.

The prognostic value of the sequential organ failure assessment (SOFA) score for critically ill elderly patients with acute infective endocarditis (IE) remains unknown. From January 2015 to December 2019, 111 elderly (≥65 years) patients with acute IE were consecutively included and divided into a low SOFA (<6) group (n = 71) and a high SOFA (≥6) group (n = 40). Endpoints included in-hospital and long-term (12-36 month) mortality. A high SOFA score was related to higher incidence of in-hospital mortality (30.0%) with an area under the curve (AUC) of 0.796. In multivariate analysis, age [odds ratio (OR) = 2.21, 95% confidence intervals (CI), 1.16-6.79, p = 0.040], SOFA ≥6 (OR = 6.38, 95% CI, 1.80-16.89, p = 0.004) and surgical treatment (OR = 0.21, 95% CI, 0.05-0.80, p = 0.021) were predictive of in-hospital mortality. A Cox proportional-hazards model identified age [Hazard ratios (HR)= 2.85, 95% CI, 1.11-7.37, p = 0.031], diabetes mellitus (HR = 3.99, 95% CI, 1.35-11.80, p = 0.013), SOFA ≥6 (OR = 3.38, 95% CI, 1.26-9.08, p = 0.001) and surgical treatment (HR = 0.24, 95% CI, 0.08-0.68, p = 0.021) as predictors of long-term mortality. A high SOFA score predicts a poor outcome including in-hospital and long-term mortality in critically ill elderly patients with acute IE.

Multicenter clinical evaluation of a piezoresistive-MEMS-sensor rapid-exchange pressure microcatheter system for fractional flow reserve measurement.

OBJECTIVES: This multicenter, prospective clinical study investigates whether the microelectromechanical-systems-(MEMS)-sensor pressure microcatheter (MEMS-PMC) is comparable to a conventional pressure wire in fractional flow reserve (FFR) measurement. BACKGROUND: As a conventional tool for FFR measurement, pressure wires (PWs) still have some limitations such as suboptimal handling characteristics and unable to maintain the wire position during pullback assessment. Recently, a MEMS-PMC compatible with any 0.014″ guidewire is developed. Compared with the existing optical-sensor PMC, this MEMS-PMC has smaller profiles at both the lesion crossing and sensor packaging areas. METHODS: Two hundred and forty-two patients with visually 30-70% coronary stenosis were enrolled at four centers. FFR was measured first with the MEMS-PMC, and then with the PW. The primary endpoint was the Bland-Altman mean bias between the MEMS-PMC and PW FFR. RESULTS: From the 224-patient per-protocol data, quantitative coronary angiography showed 17.9% and 55.9% vessels had diameter < 2.5 mm and stenosis >50%, respectively. The two systems' mean bias was -0.01 with [-0.08, 0.06] 95% limits-of-agreement. Using PW FFR≤0.80 as cutoff, the MEMS-PMC per-vessel diagnostic accuracy was 93.4% [95% confidence interval: 89.4-96.3%]. The MEMS-PMC's success rate was similar to that of PW (97.5 vs. 96.3%, p = .43) with no serious adverse event, and its clinically-significant (>0.03) drift rate was 43% less (9.5 vs. 16.7%, p = .014). CONCLUSIONS: Our study showed the MEMS-PMC is safe to use and has a minimal bias equal to the resolution of current FFR systems. Given the MEMS-PMC's high measurement accuracy and rapid-exchange nature, it may become an attractive new tool facilitating routine coronary physiology assessment.

Satisfactory Long-term Outcomes of Thoracic Endovascular Aortic Repair With a Bare Stent for Acute Complicated Type B Aortic Dissections.

PURPOSE: To compare the clinical outcomes after thoracic endovascular aortic repair (TEVAR) with a bare stent to those after TEVAR alone in patients with complicated acute type B aortic dissection (cATBAD). MATERIALS AND METHODS: A prospective, randomized trial was conducted at 2 medical centers in China between 2010 and 2013. Patients with cATBAD were randomly assigned to receive TEVAR with a bare stent (n=42) or TEVAR only (n=42). Patients were scheduled to undergo computed tomography angiography at 3, 6, and 12 months and then annually to 5 years. The primary endpoint was all-cause mortality at 5 years; secondary outcomes were a composite of complications (endoleak, stent-graft-induced new entry, aortic rupture, and secondary intervention) and aortic remodeling at 1 and 5 years. RESULTS: All-cause death occurred in 1 (2.4%) patient in the TEVAR with bare stent group (lung cancer) and 5 patients (11.9%) in the TEVAR group (4 aorta-related) during the 5-year follow-up (log-rank p=0.025). The 1- and 5-year rates of complications and secondary interventions did not differ between the groups. Patients in the TEVAR with bare stent group had higher increases in the thoracic true lumen diameter (19.7±3.6 vs 17.0±6.2 mm, p=0.018) and abdominal true lumen diameter (13.7±4.8 vs 7.2±6.1 mm, p<0.001) and a higher incidence of complete false lumen thrombosis (80.9% vs 47.6%, p=0.005) at the 1-year follow-up. However, no between-group differences in the changes of aortic remodeling parameters were observed between the 1- and 5-year follow-up periods. CONCLUSION: The addition of a distal bare stent to a thoracic stent-graft during TEVAR was associated with significantly improved long-term survival in cATBAD patients vs TEVAR only, likely due to the prevention of true lumen collapse and improvement of complete false lumen thrombosis of the dissected aorta.

Drug-coated balloon versus drug-eluting stent for treating de novo coronary lesions in large vessels: a meta-analysis of clinical trials.

BACKGROUND: Studies examining the efficiency of drug-coated balloon (DCB) compared to drug-eluting stents (DES) for de novo lesions in large vessels have reported inconsistent results. OBJECTIVE: This comprehensive meta-analysis of clinical trials compared the efficacy and safety of DCB and DES for the treatment of de novo coronary lesions. METHODS: The authors formally searched electronic databases before October 2019 to identify randomized and non-randomized clinical trials (RCTs and non-RCTs, respectively). Clinical trials were eligible for inclusion if they compared DCB with DES in patients with coronary lumen diameters >2.5 mm. RESULTS: Three RCTs and one non-RCT with a total of 321 patients were included in our meta-analysis (DCB group = 152, DES group = 169). The primary endpoint was in-segment late lumen loss (LLL) with a standardized mean difference (SMD) of -0.07 (95% confidence interval [CI]: -0.31, 0.316; P = 0.548) and the secondary endpoint was target lesion revascularization (TLR) with a risk ratio (RR) of 1.17 (95% CI: 0.46, 2.95; P = 0.746). CONCLUSION: This meta-analysis indicated that DCB might be non-inferior to DES as evidenced by quantitative coronary angiography (QCA) assessed at 6-9 months after percutaneous coronary intervention in patients presenting with coronary artery disease.

Feasibility and Safety of the Distal Transradial Artery for Coronary Diagnostic or Interventional Catheterization.

BACKGROUND: This prospective study compared the success rate and safety of a distal transradial artery (dTRA) approach to that of the conventional transradial artery (TRA) for coronary angiography or percutaneous coronary intervention. METHODS: From January 2019 to April 2020, nine hundred consecutive patients (height < 190 cm) scheduled for coronary angiography or percutaneous coronary interventions were randomly and equally assigned to receive either dTRA or conventional TRA catheterization. RESULTS: Successful access was achieved in 96.00% and 96.67% of the dTRA and conventional TRA groups, respectively (P=0.814). Compared with the TRA group, patients in the dTRA experienced significantly less hemostatic band removal time (150.5 ± 50.5 cf. 210.6 ± 60.5 min, P=0.032); minor bleeding of the access site (2.44% cf. 6.44%, P=0.038); hemostatic band cost (USD; 0.1 cf. 59.4, P=0); and postprocedural radial artery occlusion (1.56% cf. 3.78%, P=0.035). A lower body mass index was a higher risk factor for dTRA access failure (odds ratio = 0.79, P=0.024), with a cutoff of 22.04 kg/m2. CONCLUSION: Compared to conventional TRA, dTRA had a comparable high success rate, with fewer associated complications. Clinicians should use the dTRA with caution in patients with low body mass index.

The effects of serum iron level without anemia on long-term prognosis of patients with coronary heart disease complicated with chronic heart failure: a retrospective cohort study.

The effects of serum iron level without anemia on long-term prognosis of patients with coronary heart disease (CHD) complicated with chronic heart failure (CHF) is still unclear. The objective of this study was to explore the effects of serum iron level without anemia on long-term prognosis of patients with CHD complicated with CHF. In this retrospective cohort study, 221 patients with CHD complicated with CHF were consecutively investigated. These patients were divided into three groups according to the tertiles of the serum iron level: low-iron group (n = 71), medium-iron group (n = 76) and high-iron group (n = 74). The overall serum iron without anemia was 13.0 ± 5.50 µmol/L and serum iron in each group was 7.58 ± 1.63 µmol/L, 11.94 ± 1.79 µmol/L, and 19.37 ± 3.81 µmol/L, respectively. Composite endpoint events were composed of major adverse cardiovascular and cerebrovascular events (MACCE), including recurrent heart failure, all-cause death, acute coronary syndrome (ACS) and ischemic stroke. The median follow-up duration was 239 days. After adjusting relevant confounding risk factors, we found that excessively low or high serum iron level is correlated to the MACCE in patients with CHD complicated with CHF and that the prognosis of patients with excessively high serum iron level is poorer than that of patients with excessively low serum iron level. We further revealed the effect of serum iron level on MACCE is U-shaped, but not linear relationship. Sensitivity analysis showed that the correlation between serum iron level and MACCE is stable. In addition, according to the test for interaction, the variables that modify the effect including CRP (P for interaction < 0.0001), diuretics (P for interaction = 0.0212) and antiplatelet drugs (P for interaction = 0.0167). This study showed that excessively low or high serum iron level without anemia is an independent risk factor of MACCE in patients with CHD complicating with CHF.

Long noncoding RNA HOTTIP promotes endothelial cell proliferation and migration via activation of the Wnt/ß-catenin pathway.

Atherosclerosis is the major cause of stroke and heart disease. However, the course and pathogenesis of atherosclerosis remains unknown. The proliferation and migration of endothelial cell play important roles in the inition and pathological progression of atherosclerosis. In this study, we demonstrated that long noncoding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP) expression level was higher in coronary artery disease (CAD) tissues than in normal arterial tissues. The expression level of HOTTIP was upregulated in the proliferating endothelial cells induced by TNF-α or PDGF-BB. Ectopic expression of HOTTIP promoted endothelial cell proliferation and also increased the expression of proliferating makers cyclin D1 and PCNA. Moreover, elevated expression of HOTTIP promoted endothelial cell migration. Downregulation expression of HOTTIP suppressed endothelial cell proliferation and migration. Furthermore, we determined that overexpression of HOTTIP induced ß-catenin expression and enhanced the downstream protein c-Myc expression in the endothelial cell. Ectopic expression of HOTTIP increased endothelial cell proliferation and migration via activation of the Wnt/ß-catenin pathway. These results suggested that HOTTIP might manipulate the endothelial cell proliferation and migration via activation of the Wnt/ß-catenin pathway.

Impact of six versus 12 months of dual antiplatelet therapy in patients with drug-eluting stent implantation after risk stratification with the residual SYNTAX score: Results from a secondary analysis of the I-LOVE-IT 2 trial.

BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation remains undetermined, especially for those at high risk of cardiac events postprocedure. OBJECTIVES: This study was aimed to investigate the impact of 6 versus 12 months of DAPT after DES implantation based on risk stratification with the residual SYNTAX score (rSS). METHODS: A total of 2737 patients in the I-LOVE-IT 2 trial were grouped according to rSS status (low rSS [rSS = 0, n = 1474] versus high rSS [rSS > 0, n = 1263]) and DAPT duration (6 months vs. 12 months). The primary endpoint was 12-month target lesion failure (TLF), and the major secondary endpoints were 12-month net adverse clinical events (NACE) and major bleeding. RESULTS: Incidences of TLF (5.2 vs. 7.4%, P = 0.01) and NACE (9.2 vs. 13.4%, P < 0.001) at 12 months were significantly higher in patients with high rSSs compared with patients with low rSSs. Landmark analysis showed that, in patients with high rSS, 12-month DAPT was associated with slightly lower risks of TLF (3.0% vs. 1.6%, P = 0.08) and NACE (7.0 vs. 4.4%, P = 0.054) compared with 6-month DAPT within 6 to 12 months after PCI. Patients with different DAPT durations had similar risks of bleeding both in the low and high rSS groups. CONCLUSIONS: Patients with high rSSs have an increased risk of TLF and NACE at 12 months after DES implantation. Twelve-month DAPT might be superior to 6-month DAPT in patients with high rSS for reducing adverse events within 6 to 12 months after PCI without excessive risk of bleeding. © 2017 Wiley Periodicals, Inc.

Imperatorin protects H9c2 cardiomyoblasts cells from hypoxia/reoxygenation-induced injury through activation of ERK signaling pathway.

BACKGROUND: Imperatorin is a compound found in plants and has been widely used in Chinese medicine for many years. It has many pharmacological effects, including the recently reported anti-apoptotic function, however, the mechanism largely remains unclear. This study is aimed to elucidate the mechanism of Imperatorin's anti-apoptotic function. METHODS: A model of hypoxia and reoxygenation (H/R) treated h9c2 cardiomyoblasts was successfully constructed. The cells were treated with H/R condition, and followed by adding Imperatorin alone, Imperatorin with ERK inhibitor and/or ERK inhibitor alone, to examine the cell viability by Cell Counting Kit-8 assay, cell apoptosis rate by flow cytometry, and ERK expression by Western-blot under different conditions. RESULTS: The results showed that imperatorin exerted protective effect on h9c2 cells from H/R injure. It was also found that it not only increased cell viability but also reduced the apoptotic rate for H/R treated h9c2 cells. The experiments also demonstrated that imperatorin could upregulate the expression levels of both ERK1 and ERK2, which is a key step in ERK signaling pathway activation. CONCLUSIONS: These findings provided evidence that imperatorin could increase the cell viability and lower apoptotic rate in H/R treated h9c2 cells, and could also enhance the expression of ERK1/ERK2, demonstrating imperatorin's protective effect on H/R injured h9c2 cells through ERK signaling pathway.

Chemokine-Like Receptor 1 Regulates the Proliferation and Migration of Vascular Smooth Muscle Cells.

BACKGROUND We aimed to explore how chemokine-like receptor 1 (CMKLR1) influences the proliferation and migration of vascular smooth muscle cells (VSMCs). MATERIAL AND METHODS Normal VSMCs, negative control VSMCs interfered by CMKLR1 gene, and VSMCs with stable knockdown of CMKLR1 gene were divided into the control group, PDGF group, negative-shRNA group, and CMKLR1-shRNA group. Both cell number counting and BrdU incorporation assays were employed to investigate the proliferation status of VSMCs. Transwell migration assay was used to measure the migration status of VSMCs. Inflammation markers, including cytokines IL-1ß, IL-6, TNF-α, and chemokines MCP-1 in VSMCs, were detected by real-time quantitative RT-PCR. Western blotting assay was used to detect protein expressions of the MAPK pathway in VSMCs. RESULTS The number of VSMCs and the OD value of BrdU in PDGF group were significantly higher than those in the control group (both P<0.05). Compared with the control and negative-shRNA group, the CMKLR1-shRNA group exhibited significantly reduced VSMCs number and BrdU OD value (both P<0.05). Transwell migration assay indicated that PDGF-BB promoted whereas CMKLR1-shRNA inhibited the migration of VSMCs. The expression of IL-1ß, IL-6, TNF-α, and MCP-1 were up-regulated in the PDGF group but down-regulated in the CMKLR1-shRNA group. Compared with normal VSMCs, the protein level of p-ERK1/2 was up-regulated in VSMCs treated with PDGF-BB, while it was down-regulated in the CMKLR1-shRNA group. CONCLUSIONS CMKLR1 exacerbated the proliferation and migration of VSMCs by activating ERK1/2.

Canthaxanthin Mitigates Cardiovascular Senescence in Vitro and in Vivo.

BACKGROUND: The number of older people in the world is increasing year by year; studies have shown that more than 90% of cardiovascular disease occurs in the older people population, indicating that aging is one of the major risks involved in the development of cardiovascular disease. Therefore, retarding the development of cardiac aging is an important strategy to prevent aging-related cardiovascular diseases. METHODS: In the current study, we examined the anti-cardiovascular aging potential of canthaxanthin in vitro and in vivo experiments. For this, a model of cardiomyocyte senescence induced by D-galactose was established, which was used to investigate the canthaxanthin's effect on cardiac premature aging. RESULTS: We found that canthaxanthin obviously mitigated the cardiomyocyte senescence in vitro. Further mechanistic studies revealed that canthaxanthin seems to alleviate cardiomyocyte senescence by regulating the autophagy process. Furthermore, the effects of canthaxanthin on cardiovascular senescence were further evaluated. We also observed that canthaxanthin mitigated cardiac aging and fibrosis in the aged mice model. CONCLUSIONS: To sum up, the current work showed that canthaxanthin could obviously alleviate cardiac premature aging, indicating that canthaxanthin could be used as a biologically active molecule for the treatment of cardiac aging and fibrosis.

Chemokine-like receptor 1 deficiency impedes macrophage phenotypic transformation and cardiac repair after myocardial infarction.

BACKGROUND: Timely and appropriate transformation of macrophage phenotypes from proinflammatory to anti-inflammatory is essential for cardiac repair after myocardial infarction (MI). Chemokine-like receptor 1 (CMKLR1), which is expressed on macrophages, is regulated by proinflammatory and anti-inflammatory stimuli. However, the contribution of CMKLR1 to macrophage phenotypic transformation and the role it plays in modulating cardiac repair after MI remain unclear. METHODS: CMKLR1 knockout (CMKLR1-/-) mice were generated by CRISPR/Cas-mediated genome engineering. A model of murine MI was induced by permanent ligation along the left anterior descending artery. Cardiac function was evaluated by echocardiography. Infarct size and collagen deposition were detected by Masson's trichrome staining. Cardiac macrophages were obtained by fluorescence-activated cell sorting. The protein and mRNA expression of associated molecules was determined by Western blotting and qRT-PCR. RESULTS: We demonstrated that macrophages highly expressed CMKLR1 and accumulated in murine infarcted hearts during the anti-inflammatory reparative phase of MI. CMKLR1 deficiency impaired cardiac function, increased infarct size, induced maladaptive cardiac remodeling, and decreased long-term survival after MI. Furthermore, CMKLR1 deficiency impeded macrophage phenotypic transformation from M1 to M2 in vivo and in vitro. In addition, we demonstrated that CMKLR1 signaling through the PI3K/Akt/mTOR pathway stimulated C/EBPß activation while simultaneously limiting NF-κB activation, thereby promoting anti-inflammatory and prohibiting proinflammatory macrophage polarization. CONCLUSIONS: Our results reveal that CMKLR1 deficiency impedes macrophage phenotypic transformation and cardiac repair after MI involving the PI3K/AKT/mTOR pathway. CMKLR1 may thus represent a potential therapeutic target for MI.

Proportion and number of incident cancer deaths in coronary artery disease.

BACKGROUND: Globally, coronary artery disease (CAD) and cancer are the leading causes of death. Studies focusing on the proportion and spectrum of cancer mortality among CAD patients are lacking. We aim to characterize the proportion and spectrum of cancer-specific mortality among patients with CAD. METHODS: We analyzed 93,797 hospitalized survivors with angiographically documented CAD between 2007 and 2020 (mean age: 62.8 ± 11.1 years, 24.7% female) from Cardiorenal ImprovemeNt II (CIN-II) cohort. RESULTS: During the median follow-up of 4.8 years (IQR: 2.6-7.5), 13,162 (14.0%) patients died after discharge. A total of 1223/7703 (15.8% of cause-specific death) CAD patients died of cancer. The three most common types of cancer-specific death were lung (36.1%), liver (13.3%), and colorectum cancer (12.8%). Furthermore, male (adjusted HR 2.38, 95% CI: 1.99-2.85) and older (≥60 vs. <60 years, adjusted HR 3.25, 95%CI 2.72-3.88) patients had a significantly increased cancer-specific mortality. CONCLUSIONS: Our data suggest that nearly one-sixth of death is accounted for cancer among CAD patients within a median follow-up of 4.8 years. Lung, liver, and colorectum cancer are top three cancer-specific mortality. Further studies are needed to reduce cancer mortality for CAD patients, especially in older and male ones. TRAIL REGISTRATION: (ClinicalTrials.gov NCT05050877).

Toxic vascular effects of polystyrene microplastic exposure.

Polystyrene microplastics (PSMPs) are some of the most common microplastic components, and the resulting pollution has become a global problem. Extensive studies have been conducted on the toxic effects of PSMPs on the heart, lungs, liver, kidneys, nerves, intestines and other tissues. However, the impact of PSMPs on vascular toxicity is poorly understood at present. The aim of this study was to reveal the vascular toxicity of microplastics (MPs). Patients were assigned to a calcification group (25 patients) or a non-calcification group (22 patients) based on the presence or absence of calcification in the thoracic aorta wall. We detected 7 polymer types in human feces. Patients with vascular calcification (VC) had higher levels of total MPs, polypropylene (PP) and polystyrene (PS) in feces than patients without VC. The thoracic aortic calcification score was significantly positively correlated with the total MP abundance (Spearman r = 0.8109, p < 0.0001), PP (Spearman r = 0.7211, p = 0.0160) and PS (Spearman r = 0.6523, p = 0.0471) in feces. We then explored the effects of PSMP exposure on normal and vitamin D3 + nicotine (VDN)-treated rats. PSMP exposure induced mild VC in normal rats and aggravated VC in VDN-treated rats. PSMP exposure disturbed the gut microbiota, causing Proteobacteria and Escherichia_Shigella to be the dominant phylum and genus, respectively. It also induced intestinal inflammatory responses in normal rats, aggravated intestinal inflammation in VDN-treated rats, impaired the intestinal mucosal barrier, and increased intestinal permeability. This study provides a theoretical basis for the risk assessment of MP-induced cardiovascular disease.