Cathepsin B (CatB) is a cysteine proteolytic enzyme widely expressed in various cells and mainly located in the lysosomes. It contributes to the pathogenesis and development of many diseases. ...However, the role of CatB in viral myocarditis (VMC) has never been elucidated. Here we generated the VMC model by intraperitoneal injection of coxsackievirus B3 (CVB3) into mice. At day 7 and day 28, we found CatB was significantly activated in hearts from VMC mice. Compared with the wild-type mice receiving equal amount of CVB3, genetic ablation of CatB (Ctsb-/-) significantly improved survival, reduced inflammatory cell infiltration, decreased serum level of cardiac troponin I, and ameliorated cardiac dysfunction, without altering virus titers in hearts. Conversely, genetic deletion of cystatin C (Cstc-/-), which markedly enhanced CatB levels in hearts, distinctly increased the severity of VMC. Furthermore, compared with the control, we found the inflammasome was activated in the hearts of wild-type mice with VMC, which was attenuated in the hearts of Ctsb-/- mice but was further enhanced in Cstc-/- mice. Consistently, the inflammasome-initiated pyroptosis was reduced in Ctsb-/- mice hearts and further increased in Cstc-/- mice. These results suggest that CatB aggravates CVB3-induced VMC probably through activating the inflammasome and promoting pyroptosis. This finding might provide a novel strategy for VMC treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cardiovascular calcification, a kind of ectopic mineralization in cardiovascular system, including atherosclerotic calcification, arterial medial calcification, valve calcification and the gradually ...recognized heart muscle calcification, is a complex pathophysiological process correlated with poor prognosis. Although several cell types such as smooth muscle cells have been proven critical in vascular calcification, the aetiology of cardiovascular calcification remains to be clarified due to the diversity of cellular origin. Fibroblasts, which possess remarkable phenotypic plasticity that allows rapid adaption to fluctuating environment cues, have been demonstrated to play important roles in calcification of vasculature, valve and heart though our knowledge of the mechanisms controlling fibroblast phenotypic switching in the calcified process is far from complete. Indeed, the lack of definitive fibroblast lineage‐tracing studies and typical expression markers of fibroblasts raise major concerns regarding the contributions of fibroblasts during all the stages of cardiovascular calcification. The goal of this review was to rigorously summarize the current knowledge regarding possible phenotypes exhibited by fibroblasts within calcified cardiovascular system and evaluate the potential therapeutic targets that may control the phenotypic transition of fibroblasts in cardiovascular calcification.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
RATIONALE:Cardiac fibrosis is a common feature in left ventricular remodeling that leads to heart failure, regardless of the etiology. Erythropoietin-producing hepatoma interactor B2 (EphrinB2), a ...pivotal bidirectional signaling molecule ubiquitously expressed in mammals, is crucial in angiogenesis during development and disease progression. Recently, EphrinB2 was reported to protect kidneys from injury-induced fibrogenesis. However, its role in cardiac fibrosis remains to be clarified.
OBJECTIVE:We sought to determine the role of EphrinB2 in cardiac fibrosis and the underlying mechanisms during the pathological remodeling process.
METHODS AND RESULTS:EphrinB2 was highly expressed in the myocardium of patients with advanced heart failure, as well as in mouse models of myocardial infarction and cardiac hypertrophy induced by angiotensin II infusion, which was accompanied by myofibroblast activation and collagen fiber deposition. In contrast, intramyocardial injection of lentiviruses carrying EphrinB2-shRNA ameliorated cardiac fibrosis and improved cardiac function in mouse model of myocardial infarction. Furthermore, in vitro studies in cultured cardiac fibroblasts demonstrated that EphrinB2 promoted the differentiation of cardiac fibroblasts into myofibroblasts in normoxic and hypoxic conditions. Mechanistically, the pro-fibrotic effect of EphrinB2 on cardiac fibroblast was determined via activating the Stat3 and TGF-β/Smad3 signaling. We further determined that EphrinB2 modulated the interaction between Stat3 and Smad3; and identified the MAD homology 2 (MH2) domain of Smad3 and the coil-coil (CC) domain and DNA binding domain (DBD) of Stat3 mediated the interaction.
CONCLUSIONS:This study uncovered a previously unrecognized pro-fibrotic role of EphrinB2 in cardiac fibrosis, which is achieved through the interaction of Stat3 with TGF-β/Smad3 signaling, implying a promising therapeutic target in fibrotic diseases and heart failure.
Objective
Patients with systemic lupus erythematosus (SLE) often have atherosclerotic complications at a young age but normal low‐density lipoprotein (LDL) levels. This study was undertaken to ...investigate the role of LDL composition in promoting early vascular aging in SLE patients.
Methods
Plasma LDL from 45 SLE patients (SLE‐LDL) and from 37 normal healthy controls (N‐LDL) was chromatographically divided into 5 subfractions (L1–L5), and the subfraction composition was analyzed. Correlations between subfraction levels and signs of early vascular aging were assessed. Mechanisms of lipid‐mediated endothelial dysfunction were explored using in vitro assays and experiments in apoE−/− mice.
Results
The L5 percentage was increased 3.4 times in the plasma of SLE patients compared with normal controls. This increased percentage of SLE‐L5 was positively correlated with the mean blood pressure (r = 0.27, P = 0.04), carotid intima‐media thickness (IMT) (right carotid IMT, r = 0.4, P = 0.004; left carotid IMT, r = 0.36, P = 0.01), pulse wave velocity (r = 0.29, P = 0.04), and blood levels of CD16+ monocytes (r = 0.35, P = 0.004) and CX3CL1 cytokines (r = 0.43, P < 0.001) in SLE patients. Matrix‐assisted laser desorption ionization–time‐of‐flight mass spectrometry analysis revealed that plasma levels of lysophosphatidylcholine (LPC) and platelet‐activating factor (PAF) were increased in SLE‐LDL and in the SLE‐L5 plasma subfraction. Injecting SLE‐LDL, SLE‐L5, or LPC into young, male apoE−/− mice caused increases in plasma CX3CL1 levels, aortic fatty‐streak areas, aortic vascular aging, and macrophage infiltration into the aortic wall, whereas injection of N‐LDL or SLE‐L1 had negligible effects (n = 3–8 mice per group). In vitro, SLE‐L5 lipid extracts induced increases in CX3CR1 and CD16 expression in human monocytes; synthetic PAF and LPC had similar effects. Furthermore, lipid extracts of SLE‐LDL and SLE‐L5 induced the expression of CX3CL1 and enhanced monocyte–endothelial cell adhesion in assays with bovine aortic endothelial cells.
Conclusion
An increase in plasma L5 levels, not total LDL concentration, may promote early vascular aging in SLE patients, leading to premature atherosclerosis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cardiac calcification is a crucial but underrecognized pathological process, greatly increasing the risk of cardiovascular diseases. Little is known about how cardiac fibroblasts, as a central ...mediator, facilitate abnormal mineralization. Erythropoietin-producing hepatoma interactor B2 (EphrinB2), previously identified as an angiogenic regulator, is involved in fibroblast activation, while its role in the osteogenic differentiation of cardiac fibroblasts is unknown. Bioinformatics analysis was conducted to characterize the expression of the Ephrin family in human calcified aortic valves and calcific mouse hearts. The effects of EphrinB2 on cardiac fibroblasts to adopt osteogenic fate was determined by gain- and loss-of-function. EphrinB2 mRNA level was downregulated in calcified aortic valves and mouse hearts. Knockdown of EphrinB2 attenuated mineral deposits in adult cardiac fibroblasts, whereas overexpression of EphrinB2 promoted their osteogenic differentiation. RNA sequencing data implied that Ca
-related S100/receptor for advanced glycation end products (RAGE) signaling may mediate EphrinB2-induced mineralization in cardiac fibroblasts. Moreover, L-type calcium channel blockers inhibited osteogenic differentiation of cardiac fibroblasts, implying a critical role in Ca
influx. In conclusion, our data illustrated an unrecognized role of EphrinB2, which functions as a novel osteogenic regulator in the heart through Ca
signaling and could be a potential therapeutic target in cardiovascular calcification.
In this study, we observed that adult cardiac fibroblasts but not neonatal cardiac fibroblasts exhibit the ability of osteogenic differentiation. EphrinB2 promoted osteogenic differentiation of cardiac fibroblasts through activating Ca
-related S100/RAGE signaling. Inhibition of Ca
influx using L-type calcium channel blockers inhibited EphrinB2-mediated calcification of cardiac fibroblasts. Our data implied an unrecognized role of EphrinB2 in regulating cardiac calcification though Ca
-related signaling, suggesting a potential therapeutic target of cardiovascular calcification.
Vascular remodeling refers to the alternations of function and structure in vasculature. A complex autocrine/paracrine set of cellular interaction is involved in vascular remodeling. Exosome, a newly ...identified natural nanocarrier and intercellular messenger, plays a pivotal role in regulating cell-to-cell communication. Exosome emerges as an important mediator in the process of vascular remodeling, showing the most prognostic and therapeutic potent in vascular diseases. Benefiting from exosomal trafficking, the vasculature can not only maintain its function and structure in physiological condition, but also adapt itself in pathological status. In this review, we will represent the roles of exosomes in angiogenesis, endothelial function and cardiac regeneration. In addition, greatly depending on the pathophysiological status of donor cells and peripheral micro-circumstance, the exosomal content could alter, which makes exosomes exhibit pleiotropic effects in vascular diseases. Hence, the diverse effects of exosomes in vascular diseases including atherosclerosis, neointima formation and vascular repair, primary hypertension, pulmonary artery hypertension, and aortic aneurysm will be discussed. Finally, the translational appliances targeting exosomes will be concluded by providing updated applications of engineered exosomes in clinic.
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Interleukin-17A, a pro-inflammatory cytokine, has a direct proapoptotic effect on cardiomyocytes. However, the specific mechanism has not been clarified. In the present study, an in-vitro model of ...cardiomyocyte apoptosis induced by IL-17A stimulation was employed and the roles of iNOS and Stat3 involved were investigated. Our data showed that the neonatal mouse cardiomyocytes express IL-17 receptors: IL-17RA and IL-17RC, but did not express IL-17A. Exogenous IL-17A significantly induces iNOS expression and hence the cardiomyocyte apoptosis. Moreover, IL-17A-induced cardiomyocyte apoptosis can be achieved directly via iNOS activation. We further showed that exogenous IL-17A simultaneously triggers Stat3 activation, which in turn inhibits IL-17A-induced iNOS expression in cardiomyocytes. And both ChIP and dual-luciferase results confirmed that Stat3 directly inhibits transcriptional activities of iNOS via binding to its specific promoter region. Consistent with these data, silencing of Stat3 in fact can aggravate IL-17A-triggered cardiomyocyte apoptosis. Finally, using an in vivo myocardial ischemia/reperfusion injury model, we verified that Stat3 inhibition increased iNOS expression and exacerbated cardiomyocyte apoptosis. Thus, our data strongly support the notion that Stat3 plays a compensatory anti-apoptotic role in IL-17A/iNOS-mediated cardiomyocyte apoptosis via inhibiting iNOS transcription, providing a novel molecular mechanism of apoptosis regulation and complicated interactions between IL-17A/iNOS and IL-17A/Stat3 signalings.
•IL-17A-induced cardiomyocyte apoptosis is achieved via iNOS activation.•IL-17A-activated Stat3 inhibits IL-17A-induced iNOS expression in cardiomyocyte.•Stat3 directly down-regulates transcription of iNOS by promoter binding in cardiomyocyte.•Stat3 inhibition increases iNOS expression and aggravates myocardial apoptosis in vivo.•The interesting mechanism implies a self-modulation model in cardiovascular system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Vascular endothelial injury (VEI) triggers pathological processes in various cardiovascular diseases, such as coronary heart disease and hypertension. To further elucidate the in vivo pathological ...mechanisms of VEI, many animal models have been established. For the easiness of genetic manipulation and feeding, murine models become most commonly applied for investigating VEI. Subsequently, countless valuable information concerning pathogenesis has been obtained and therapeutic strategies for VEI have been developed. This review will highlight some typical murine VEI models from the perspectives of pharmacological intervention, surgery and genetic manipulation. The techniques, pathophysiology, advantages, disadvantages and the experimental purpose of each model will also be discussed.
•This review summarized three types of murine vascular endothelial injury models.•The detailed techniques and potential pathophysiological mechanisms are described.•The surgical models with the most difficulties to operate among these models are graphically explained.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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