Hypercholesterolaemic Serum Increases the Permeability of Endothelial Cells through Zonula Occludens-1 with Phosphatidylinositol 3-Kinase Signaling Pathway

Purpose. Hypercholesterolemia and tight junctions play important roles in atherosclerosis. But the relationship between these two factors is unclear. In the present study, we investigated whether hypercholesterolemic serum could change the permeability of endothelial cells through altering expression and/or distribution of tight junction protein zonula occludens-1 (ZO-1). Phosphatidylinositol 3-kinase (PI3K) signaling pathway was also examined. Materials and Methods. Cultured endothelial cells were treated with different concentration levels of hypercholesterolemic serum. The expression and distribution of ZO-1, the permeability of cultured cells and the involvement of PI3K signaling pathway were measured by various methods. Results. In the present study, we found that hypercholesterolemic serum could not change the expression of ZO-1 either in mRNA or protein level. However, hypercholesterolemic serum could change the distribution of ZO-1 in cultured endothelial cells, and increase the permeability with a dose-dependent manner. When PI3K specific inhibitor wortmannin was used, the effects induced by hypercholesterolemic serum could be partly reversed. The role of PI3K signaling pathway was further confirmed by PI3K activity assay. Conclusions. Our results suggested that although hypercholesterolemic serum could not change the expression of ZO-1, it could change the distribution and increase the permeability in endothelial cells through PI3K signaling pathway

IgE actions on CD4+ T cells, mast cells, and macrophages participate in the pathogenesis of experimental abdominal aortic aneurysms

Immunoglobulin E (IgE) activates mast cells (MCs). It remains unknown whether IgE also activates other inflammatory cells, and contributes to the pathogenesis of abdominal aortic aneurysms (AAAs). This study demonstrates that CD4+ T cells express IgE receptor FcεR1, at much higher levels than do CD8+ T cells. IgE induces CD4+ T-cell production of IL6 and IFN-γ, but reduces their production of IL10. FcεR1 deficiency (Fcer1a−/−) protects apolipoprotein E-deficient (Apoe−/−) mice from angiotensin-II infusion-induced AAAs and reduces plasma IL6 levels. Adoptive transfer of CD4+ T cells (but not CD8+ T cells), MCs, and macrophages from Apoe−/− mice, but not those from Apoe−/− Fcer1a−/− mice, increases AAA size and plasma IL6 in Apoe−/− Fcer1a−/− recipient mice. Biweekly intravenous administration of an anti-IgE monoclonal antibody ablated plasma IgE and reduced AAAs in Apoe−/− mice. Patients with AAAs had significantly higher plasma IgE levels than those without AAAs. This study establishes an important role of IgE in AAA pathogenesis by activating CD4+ T cells, MCs, and macrophages and supports consideration of neutralizing plasma IgE in the therapeutics of human AAAs

Cystatin C Deficiency Promotes Epidermal Dysplasia in K14-HPV16 Transgenic Mice

Cysteine protease cathepsins are important in extracellular matrix protein degradation, cell apoptosis, and angiogenesis. Mice lacking cathepsins are protected from tumor progression in several animal models, suggesting that the regulation of cathepsin activities controls the growth of various malignant tumors.We tested the role of cathepsins using a mouse model of multistage epithelial carcinogenesis, in which the human keratin-14 promoter/enhancer drove the expression of human papillomavirus type 16 (HPV16) early region E6/E7 transgenes. During the progression of premalignant dysplasia, we observed increased expression of cysteine protease cathepsin S, but concomitantly reduced expression of cathepsin endogenous inhibitor cystatin C in the skin tissue extract. Absence of cystatin C in these transgenic mice resulted in more progression of dysplasia to carcinoma in situ on the face, ear, chest, and tail. Chest and ear skin extract real time PCR and immunoblot analysis, mouse serum sample ELISA, tissue immunohistological analysis, and tissue extract-mediated in vitro elastinolysis and collagenolysis assays demonstrated that cystatin C deficiency significantly increased cathepsin expression and activity. In skin from both the chest and ear, we found that the absence of cystatin C reduced epithelial cell apoptosis but increased proliferation. From the same tissue preparations, we detected significantly higher levels of pro-angiogenic laminin 5-derived γ2 peptides and concurrently increased neovascularization in cystatin C-deficient mice, compared to those from wild-type control mice.Enhanced cathepsin expression and activity in cystatin C-deficient mice contributed to the progression of dysplasia by altering premalignant tissue epithelial proliferation, apoptosis, and neovascularization

Phosphoenolpyruvate carboxykinase in cell metabolism: Roles and mechanisms beyond gluconeogenesis

Background: Phosphoenolpyruvate carboxykinase (PCK) has been almost exclusively recognized as a critical enzyme in gluconeogenesis, especially in the liver and kidney. Accumulating evidence has shown that the enhanced activity of PCK leads to increased glucose output and exacerbation of diabetes, whereas the defects of PCK result in lethal hypoglycemia. Genetic mutations or polymorphisms are reported to be related to the onset and progression of diabetes in humans. Scope of review: Recent studies revealed that the PCK pathway is more complex than just gluconeogenesis, depending on the health or disease condition. Dysregulation of PCK may contribute to the development of obesity, cardiac hypertrophy, stroke, and cancer. Moreover, a regulatory network with multiple layers, from epigenetic regulation, transcription regulation, to posttranscription regulation, precisely tunes the expression of PCK. Deciphering the molecular basis that regulates PCK may pave the way for developing practical strategies to treat metabolic dysfunction. Major conclusions: In this review, we summarize the metabolic and non-metabolic roles of the PCK enzyme in cells, especially beyond gluconeogenesis. We highlight the distinct functions of PCK isoforms (PCK1 and PCK2), depict a detailed network regulating PCK's expression, and discuss its clinical relevance. We also discuss the therapeutic potential targeting PCK and the future direction that is highly in need to better understand PCK-mediated signaling under diverse conditions

The Association between Serum Creatinine/Cystatin C Ratio and Cardiovascular Morbidity and Mortality: Insights from NHANES

Background: The Serum creatinine/cystatin C ratio (Cr/CysC ratio) is an emerging alternative index for muscle mass loss, a risk factor for cardiovascular diseases (CVDs). However, the association between the Cr/CysC ratio and CVD morbidity and mortality remains unknown. Methods: A total of 11,150 participants of the National Health and Nutrition Examination Survey (NHANES) were included in this study. Univariable and multivariable logistic regression models were employed to assess the association between the Cr/CysC ratio and self-reported CVD morbidity. Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the Cr/CysC ratio for CVD mortality. Results: At baseline, 1181 (7.90%) participants had self-reported CVDs. Lower Cr/CysC ratios were found in participants with CVDs (1.18 ± 0.30 vs. 1.05 ± 0.23, p < 0.001). In the multivariable logistic regression model, the Cr/CysC ratio was inversely linked to CVD morbidity (odds ratio: 0.65, 95% CI: 0.52–0.81, p < 0.001, per standard deviation [SD] increase). 997 (8.94%) CVD deaths were documented during a median follow-up of 16.9 years. A higher Cr/CysC ratio was associated with a decreasing risk of CVD mortality (adjusted HR: 0.54, 95% CI: 0.46–0.65, p < 0.001, per SD increase). Conclusions: In NHANES participants, the Cr/CysC ratio had an inverse correlation with CVD morbidity and mortality

The Prevalence and Characteristics of Mitral Regurgitation in Heart Failure: A Chart Review Study

Background: Mitral regurgitation (MR) is one of the common complications of heart failure (HF). The prevalence and characteristics of MR are rarely investigated, especially in the Chinese population. Objectives: The purpose of this study was to determine the prevalence and characteristics of non-organic MR in HF patients and subgroups defined by ejection fraction. Methods: A single-center, hospital-based, and retrospective chart review study included patients with heart failure admitted to the cardiovascular department from January 2017 to April 2020. Demographic characteristics, laboratory results, and echocardiogram results before discharge were analyzed in different groups defined by left ventricular ejection fraction (EF) using logistic regression and adjusted for confounders. Results: Finally, 2418 validated HF patients (age 67.2 ± 13.5 years; 68.03% men) were included. The prevalence of MR was 32.7% in HF, 16.7% in HF with preserve EF patients, 28.4% in HF with mid-range EF patients and 49.7% in HF with reduced EF (HFrEF) patients. In the HF with preserved EF group, multivariable logistic regression showed that 4 factors associated with MR including EF (odds ratio (OR) 0.954 (0.928–0.981), p = 0.001), left ventricular posterior wall thickness in diastolic phase (LVPWd) (OR 0.274 (0.081–0.932), p = 0.038), left atrium (LA) dimension (OR 2.049 (1.631–2.576), p < 0.001) and age (OR 1.024 (1.007–1.041), p = 0.007). In the HF with midrange EF group, multivariable logistic regression showed that 3 factors associated with MR including LA dimension (OR 2.009 (1.427–2.829), p < 0.001), triglycerides (TG) (OR 0.552 (0.359–0.849), p = 0.007) and digoxin (OR 2.836 (1.624–4.951), p < 0.001). In the HFrEF group, multivariable logistic regression showed that 7 factors associated with MR including EF (OR 0.969 (0.949–0.990), p = 0.004), (OR 0.161 (0.067–0.387), p < 0.001), LA dimension (OR 2.289 (1.821–2.878), p < 0.001), age (OR 1.016 (1.004–1.027)), p = 0.009), TG (OR 0.746 (0.595–0.936), p = 0.011), diuretics (OR 0.559 (0.334–0.934), p = 0.026) and ICD (OR 1.898 (1.074–3.354), p = 0.027). Conclusions: HF patients had a high burden of MR, particularly in the HFrEF group. Worsen cardiac structure (LA dimension and LVPWd) and function (EF), age, and medical treatment strategy played essential roles in MR

Independent Association of Thyroid Dysfunction and Inflammation Predicts Adverse Events in Patients with Heart Failure via Promoting Cell Death

Thyroid dysfunction and inflammation are individually implicated in the increased risk of heart failure. Given the regulatory role of thyroid hormones on immune cells, this study aimed to investigate their joint association in heart failure. Patients with pre-existing heart failure were enrolled when hospitalized between July 2019 and September 2021. Thyroid function and inflammatory markers were measured at the enrollment. The composite of all-cause mortality or rehospitalization for heart failure were studied in the following year. Among 451 participants (mean age 66.1 years, 69.4% male), 141 incident primary endpoints were observed during a median follow-up of 289 days. TT3 and FT3 levels were negatively correlated with BNP levels (r: −0.40, p p p p < 0.001). Multivariate COX regression analysis revealed that FT3 (adjusted HR: 0.677, 95% CI: 0.551–0.832) and NLR (adjusted HR: 1.073, 95% CI: 1.036–1.111) were associated with adverse event, and similar results for TT3 (adjusted HR: 0.320, 95% CI: 0.181–0.565) and NLR (adjusted HR: 1.072, 95% CI: 1.035–1.110). Restricted cubic splines analysis indicated a linear relationship between T3 level and adverse events. Mechanistically, primary cardiomyocytes showed strong resistance to TNF-α induced apoptosis under optimal T3 concentrations, as evidenced by TUNEL staining, flow cytometry analysis, and LDH release assay as well as increased expression of Bcl-2. Thyroid dysfunction and inflammation are independently associated with cardiovascular risk in heart failure patients, which may concurrently contribute to the ongoing cardiomyocyte loss in the disease progression

Essential roles of EphrinB2 in mammalian heart: from development to diseases

Abstract EphrinB2, a membrane-tethered ligand preferentially binding to its receptor EphB4, is ubiquitously expressed in all mammals. Through the particular bidirectional signaling, EphrinB2 plays a critical role during the development of cardiovascular system, postnatal angiogenesis physiologically and pathologically, and cardiac remodeling after injuries as an emerging role. This review highlights the pivotal involvement of EphrinB2 in heart, from developmental cardiogenesis to pathological cardiac remodeling process. Further potential translational therapies will be discussed in targeting EphrinB2 signaling, to better understand the prevention and treatment of cardiovascular diseases