Exosomes derived from human umbilical cord mesenchymal stem cells (HUCMSC-EXO) regulate autophagy through AMPK-ULK1 signaling pathway to ameliorate diabetic cardiomyopathy.

One of the main causes of severe diabetic heart failure and mortality is diabetic cardiomyopathy (DCM), a cardiovascular condition attributable to diabetes with a high incidence, a complicated and unexplained pathophysiology, and poor treatment results. Current findings have demonstrated that the onset of diabetic cardiomyopathy involves autophagy, inflammation, and mitochondrial damage. Myocardial autophagy behaves differently in different states,and one of the targets for the detection and treatment of cardiovascular illnesses like diabetic cardiomyopathy may be the control of autophagy. The role of human umbilical cord Mesenchymal stem cells-derived exosomes (HUCMSC-EXO) as a non-cellular system in the repair of cardiomyocytes, the evolution of diabetic cardiomyopathy and their cardioprotective effects are gradually being recognized. This study's objectives were to assess the therapeutic benefits of HUCMSC-EXO for diabetic cardiomyopathy and to look into their potential mechanisms of action. High-speed centrifugation was used to extract HUCMSC-EXO, and the shape of the exosomes was examined using transmission electron microscopy. Immunoblotting was used to determine the expression of CD9, CD63, and TSG101 molecules on the surface of the exosomes. A high-fat, high-sugar diet mixed with streptozotocin was used to build a rat model of type 2 diabetic cardiomyopathy. Cardiac function, ventricular wall thickness and cardiac histological changes were examined by cardiac ultrasound, serum BNP and histology. In cardiac myocytes, HUCMSC-EXO reduced the levels of autophagy-related protein expression. Additionally, immunoblotting supported our suspicion that this mechanism is strongly tied to the activation of the AMPK-ULK1 signaling pathway. So, we propose that it would be a good strategy to follow for treating diabetic cardiomyopathy. These findings offer both fresh concepts for building a model of diabetic cardiomyopathy and a creative theoretical framework for using HUCMSC-EXO to treat diabetic cardiomyopathy in a clinical setting.

Quercetin exerts cardiovascular protective effects in LPS-induced dysfunction in vivo by regulating inflammatory cytokine expression, NF-κB phosphorylation, and caspase activity.

Impaired myocardial contractile function, one of the well-documented features of sepsis, contributes greatly to the high rate of mortality. Quercetin is widely accepted as a potential antioxidant and free radical scavenger. Epidemiologic studies have suggested that an increase in the intake of dietary Quercetin can reduce the risk of cardiac disease. However, presently there is no report yet on the influence of Quercetin on LPS-induced myocardial dysfunction in vivo. Cardiovascular protective effects of Quercetin on LPS-induced sepsis in mice were measured after intragastric administration, using normal saline as a positive control. Quercetin pretreatment significantly alleviated LPS-induced cardiac abnormalities in mice. The histopathologic findings in the present study justify the findings reported from the biochemical analyses. Our observation from the present research work reveals that Quercetin suppressed the production of proinflammatory cytokines at different levels, such as TNF-α and IL-1ß, and inhibits the activation of I-κB phosphorylation, whereas the total content was not affected. Apoptotic pathways are related to Quercetin protection in the development of myocardial dysfunction. In conclusion, our findings demonstrate the adjuvant potentials of Quercetin for clinical sepsis treatment.

Drug-coated balloons for treating de novo lesions in large coronary vessels: A case report.

BACKGROUND: Percutaneous transluminal coronary angioplasty, while an effective intervention, can frequently lead to acute occlusion with severe consequences. Although clinical trials have demonstrated the efficacy of drug-coated balloons (DCB) in treating acute coronary artery occlusion and in preventing restenosis, there has been limited exploration on the use of DCB in treating de novo lesions in large vessels. Currently, DCB are only recommended for patients with small vessel lesions and in-stent restenosis lesions, those at high risk of bleeding, and other special groups of patients. CASE SUMMARY: This report presents a case of successful drug-coated balloon treatment of de novo lesions in large coronary vessels. Postoperatively, the patient demonstrated favorable recovery, with subsequent examination results revealing no significant differences from the previous examination. CONCLUSION: The successful treatment of the patient in our case highlights the potential of DCB in the treatment of de novo lesions in large coronary vessels.

Astragaloside IV Inhibits NLRP3 Inflammasome-Mediated Pyroptosis via Activation of Nrf-2/HO-1 Signaling Pathway and Protects against Doxorubicin-Induced Cardiac Dysfunction.

BACKGROUND: Doxorubicin (DOX) is an effective broad-spectrum antitumor drug, but its clinical application is limited due to the side effects of cardiac damage. Astragaloside IV (AS-IV) is a significant active component of Astragalus membranaceus that exerts cardioprotective effects through various pathways. However, whether AS-IV exerts protective effects against DOX-induced myocardial injury by regulating the pyroptosis is still unknown and is investigated in this study. METHODS: The myocardial injury model was constructed by intraperitoneal injection of DOX, and AS-IV was administered via oral gavage to explore its specific protective mechanism. Cardiac function and cardiac injury indicators, including lactate dehydrogenase (LDH), cardiac troponin I (cTnI), creatine kinase isoenzyme (CK-MB), and brain natriuretic peptide (BNP), and histopathology of the cardiomyocytes were assessed 4 weeks post DOX challenge. Serum levels of IL-1ß, IL-18, superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) and the expression of pyroptosis and signaling proteins were also determined. RESULTS: Cardiac dysfunction was observed after the DOX challenge, as evidenced by reduced ejection fraction, increased myocardial fibrosis, and increased BNP, LDH, cTnI, and CK-MB levels (p < 0.05, N = 3-10). AS-IV attenuated DOX-induced myocardial injury. The mitochondrial morphology and structure were also significantly damaged after DOX treatment, and these changes were restored after AS-IV treatment. DOX induced an increase in the serum levels of IL-1ß, IL-18, SOD, MDA and GSH as well as an increase in the expression of pyroptosis-related proteins (p < 0.05, N = 3-6). Besides, AS-IV depressed myocardial inflammatory-related pyroptosis via activation of the expressions of nuclear factor E2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) (p < 0.05, N = 3). CONCLUSIONS: Our results showed that AS-IV had a significant protective effect against DOX-induced myocardial injury, which may be associated with the activation of Nrf-2/HO-1 to inhibit pyroptosis.

Soluble programmed cell death-ligand 1 as a new potential biomarker associated with acute coronary syndrome.

Background: Soluble programmed cell death-ligand 1 (sPD-L1) has been well documented to activate immunosuppression and is considered an essential predictor of negative clinical outcomes for several malignances and inflammatory conditions. However, the clinical significance of sPD-L1 in the peripheral blood of patients with coronary artery disease (CAD) remains unclear. The aim of this study was to assess the correlations of sPD-L1 with clinical features in CAD patients and evaluate the diagnostic value of this protein in CAD. Methods: A total of 111 CAD patients and 97 healthy volunteers who served as healthy controls (HCs) were consecutively enrolled. Plasma levels of sPD-L1 were measured with an amplified enzyme-linked immunosorbent assay (ELISA), and hs-CRP was measured with a C-reactive protein assay kit. The levels of other inflammatory cytokines were assessed in 88 CAD patients and 47 HCs by a multiparameter immunoluminescence flow cytometry detection technique. A logistic regression model was used to assess the independent association of sPD-L1 with acute coronary syndrome (ACS). The correlation between sPD-L1 and inflammatory cytokines in ACS was also assessed. Results: Plasma levels of sPD-L1 were significantly increased in CAD patients, especially those with ACS. Univariate logistic regression analysis revealed that sPD-L1 (OR: 3.382, 95% CI: 2.249-5.084, p < 0.001), BMI, hypertension, diabetes, dyslipidemia, previous MI, and the levels of HDL-C, LDL-C and hs-CRP were significantly associated with ACS. sPD-L1 (OR: 3.336, 95% CI: 1.084-6.167, p = 0.001) was found to be independently and significantly associated with ACS in the subsequent multivariable logistic regression analysis. Additionally, elevated plasma sPD-L1 levels were associated with increased interleukin-6 and interleukin-8 levels in ACS patients. Receiver operating characteristic (ROC) analysis showed that the AUC of sPD-L1 for diagnosing ACS was 0.778, with a sensitivity of 73.9% and a specificity of 73.4%, which was comparable with that of the inflammatory biomarker hs-CRP. Conclusion: The plasma sPD-L1 level reflects the severity of CAD, is associated with inflammatory responses and is a potential new biomarker for the diagnosis of ACS.

Prognostic value of left ventricular hypertrophy in hypertensive patients: A meta-analysis of electrocardiographic studies.

Electrocardiographic left ventricular hypertrophy (LVH) has been used to predict adverse outcomes in different clinical settings. This meta-analysis aimed to compare the prognostic value of different electrocardiographic criteria of LVH at baseline in hypertensive patients. A systematic literature search was conducted in PubMed and Embase databases until December 3, 2019. Cohort studies that reported the association of baseline electrocardiographic LVH (Sokolow-Lyon voltage, Cornell voltage or Cornell product) with all-cause mortality or major cardiovascular events in hypertensive patients were included. The prognostic value of LVH was expressed by the risk ratio (RR) with 95% confidence interval (CI). Nine studies involving 41 870 hypertensive patients were identified. Comparison with those with and without LVH patients indicated that the pooled RR value of all-cause mortality was 1.30 (95% CI 1.01-1.66) for the Sokolow-Lyon voltage criteria, 1.33 (95% CI 1.20-1.47) for the Cornell voltage criteria, and 1.31 (95% CI 0.97-1.78) for the Cornell product criteria. In addition, the pooled RR of major cardiovascular events was 1.53 (95% CI 1.27-1.86) for the Sokolow-Lyon criteria and 1.46 (95% CI 1.22-1.76) for the Cornell voltage criteria, respectively. This meta-analysis suggests that different electrocardiographic criteria for detecting LVH at baseline differ in prediction of all-cause mortality in patients with hypertension. LVH detected by the Cornell voltage and Sokolow-Lyon criteria can independently predict the major cardiovascular events in hypertensive patients.

Astragaloside IV Exerts a Myocardial Protective Effect against Cardiac Hypertrophy in Rats, Partially via Activating the Nrf2/HO-1 Signaling Pathway.

Previous evidence suggested that astragaloside IV (ASIV) had a cardioprotective effect, but the potential mechanisms were undetermined. This study is aimed at validating the prevention of cardiac hypertrophy in chronic heart failure (CHF) rats and hypertrophy in H9c2 cardiomyocytes by ASIV and at exploring the potential mechanism involved. CHF rat models of abdominal aortic constriction (AAC) were used with the aim of determining the protective effect of ASIV in cardiac hypertrophy in the rats. We proved that ASIV could attenuate cardiac hypertrophy by improving left ventricular function and structure and showed that the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) and its downstream gene heme oxygenase-1 (HO-1) increased in the high-dose ASIV intervention group. To further investigate the specific mechanism of ASIV, we hypothesized that ASIV might prevent cardiac hypertrophy via activating the Nrf2/HO-1 signaling pathway. We established a cardiomyocyte hypertrophy model induced by angiotensin II (Ang II), which was then transfected with Nrf2 shRNA, to knock down the expression of the Nrf2 gene. We found that the protective effect of ASIV against Ang II-induced cardiomyocyte hypertrophy was abolished in the Nrf2 shRNA transfection group, ultimately aggravating cardiomyocyte hypertrophy induced by Ang II, and it is possible that oxidative stress may be involved in this process. Our results demonstrated that ASIV improved cardiac function and inhibited cardiac hypertrophy by upregulating Nrf2, and this effect was partially achieved by stimulating the Nrf2/HO-1 signaling pathway, suggesting that ASIV could have therapeutic potential for the treatment of cardiac hypertrophy and CHF.

Astragaloside IV inhibits ventricular remodeling and improves fatty acid utilization in rats with chronic heart failure.

Chronic heart failure (CHF) is the end-stage of many cardiovascular diseases and severely affects the patients' lifespan. Inhibiting ventricular remodeling is thus a primary treatment target for CHF patients. Astragaloside IV (AS-IV) can improve cardiac function and protect myocardial cells. The study aims to investigate the effects of AS-IV on ventricular remodeling and explore its role in regulating energy metabolism using a rat CHF model. Sprague-Dawley rats were divided into five groups (n=20 per group): CHF + benazepril hydrochloride (Benazepril HCL), CHF + low-dose (30 mg.kg-1day-1) AS-IV, CHF + high-dose (60 mg.kg-1day-1) AS-IV, and a sham control group. After 8 weeks of treatment, the cardiac structure and functional parameters were measured. Morphological changes in the myocardial tissue in five groups were evaluated. Protein and mRNA expression of peroxisome proliferator-activated receptor α (PPARα), medium-chain acyl-CoA dehydrogenase (MCAD), and muscle carnitine palmitoyl transferase-1 (MCPT1) were also analyzed. Our results showed that the left ventricular mass index (LVMI), collagen volume fraction (CVF), and free fatty acid (FFA) concentration of CHF group rats increased when compared with sham control group, while the protein and mRNA expressions of PPARα, MCAD, and MCPT1 decreased in CHF. Importantly, treatment with AS-IV (CHF + AS-IV group) showed improved heart function and structure, increased expression of PPARα, MCAD, and MCPT1 and improved FFA utilization in comparison with CHF group. In conclusion, our study shows that AS-IV inhibits ventricular remodeling, improves cardiac function, and decreases FFA concentration of CHF model rats. Our findings suggest a therapeutic potential of using AS-IV in CHF.

Honokiol Protects against Anti-ß1-Adrenergic Receptor Autoantibody-Induced Myocardial Dysfunction via Activation of Autophagy.

Myocardial diseases are prevalent syndromes with high mortality rate. The exploration of effective interference is important. Anti-ß1-adrenergic receptor autoantibody (ß1-AAB) is highly correlated with myocardial dysfunction. The actions and underlying mechanisms of honokiol (HNK) in ß1-AAB-positive patients await to be unraveled. In this study, we established a rat model of ß1-AAB positive with myocardial dysfunction. Cardiac function following ß1-AR-ECII administration was analyzed using the VisualSonics Vevo 770 High-Resolution In Vivo Imaging System. The levels of autophagy-related proteins were detected by Western blotting. Our data revealed that HNK reversed ß1-AAB-induced effects and protected myocardial tissues from dysfunction. After HNK treatment, the cardiac contractile ability increased and the LDH activity decreased. HNK attenuated myocardial degeneration. In addition, HNK promoted the activation of the AMP-dependent protein kinase/Unc-51-like autophagy activating kinase (AMPK/ULK) pathway and activated autophagy. These results suggest that HNK protects against ß1-AAB-induced myocardial dysfunction via activation of autophagy and it may be a potentially therapeutic compound for ß1-AAB-positive myocardial diseases.

Metformin ameliorates hypoxia/reoxygenation-induced cardiomyocyte apoptosis based on the SIRT3 signaling pathway.

Myocardial hypoxia/reoxygenation (H/R) injury is one of the main causes of death and disability worldwide. However, a limited number of therapies are available to minimize the detrimental effects of this injury. Recently, researchers have demonstrated that metformin exerts direct cardioprotective effects against H/R. The aim of this study was to investigate the underlying mechanisms of how metformin affects myocardial hypoxia/reoxygenation (H/R) injury. In our study, the activities of lactate dehydrogenase (LDH) and superoxide dismutase (SOD) as well as the levels of malondialdehyde (MDA) were measured. Following H/R injury, LDH activity and MDA levels were evidently increased, while SOD activity and cell viability significantly decreased. Surprisingly, metformin downregulated the levels of relative reactive oxygen species (ROS) and upregulated the levels of relative SOD following H/R injury. Furthermore, metformin-treated cells exhibited reduced cell death, which was demonstrated to be associated with increased SIRT3 expression compared to that in the control group, as evidenced by blocking of the protective effects of metformin on cell apoptosis by the SIRT3 inhibitor Nicotinamide (NAM). Therefore, our results demonstrate that metformin improves cells viability following H/R, and this cardioprotective effect is partly mediated by the SIRT3 signaling pathway.