Immunoproteasome subunit ß5i regulates diet-induced atherosclerosis through altering MERTK-mediated efferocytosis in Apoe knockout mice.

The immunoproteasome contains three catalytic subunits (ß1i, ß2i and ß5i) that are important modulators of immune cell homeostasis. A previous study showed a correlation between ß5i and human atherosclerotic plaque instability; however, the causative role of ß5i in atherosclerosis and the underlying mechanisms remain unknown. Here we explored this issue in apolipoprotein E (Apoe) knockout (eKO) mice with genetic deletion or pharmacological inhibition of ß5i. We found that ß5i expression was upregulated in lesional macrophages after an atherogenic diet (ATD). ß5i/Apoe double KO (dKO) mice fed on the ATD had a significant decrease in both lesion area and necrotic core area, compared with eKO controls. Moreover, dKO mice had less caspase-3+ apoptotic cell accumulation but enhanced efferocytosis of apoptotic cells and increased expression of Mer receptor tyrosine kinase (MERTK). Consistently, similar phenotypes were observed in eKO mice transplanted with dKO bone marrow or treated with ß5i-specific inhibitor PR-957. Mechanistic studies in vitro revealed that ß5i deletion reduced IκBα degradation and inhibited NF-κB activation, promoting Mertk transcription and efferocytosis, thereby attenuating apoptotic cell accumulation. In conclusion, we demonstrate that ß5i plays an important role in diet-induced atherosclerosis by altering MERTK-mediated efferocytosis. ß5i might be a potential pharmaceutical target against atherosclerosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

IL-18 cleavage triggers cardiac inflammation and fibrosis upon ß-adrenergic insult.

Aims: Rapid over-activation of ß-adrenergic receptor (ß-AR) upon stress leads to cardiac inflammation, a prevailing factor that underlies heart injury. However, mechanisms by which acute ß-AR stimulation induce cardiac inflammation still remain unknown. Here, we set out to identify the crucial role of inflammasome/interleukin (IL)-18 in initiating and maintaining cardiac inflammatory cascades upon ß-AR insult. Methods and results: Male C57BL/6 mice were injected with a single dose of ß-AR agonist, isoproterenol (ISO, 5 mg/kg body weight) or saline subcutaneously. Cytokine array profiling demonstrated that chemokines dominated the initial cytokines upregulation specifically within the heart upon ß-AR insult, which promoted early macrophage infiltration. Further investigation revealed that the rapid inflammasome-dependent activation of IL-18, but not IL-1ß, was the critical up-stream regulator for elevated chemokine expression in the myocardium upon ISO induced ß1-AR-ROS signalling. Indeed, a positive correlation was observed between the serum levels of norepinephrine and IL-18 in patients with chest pain. Genetic deletion of IL-18 or the up-stream inflammasome component NLRP3 significantly attenuated ISO-induced chemokine expression and macrophage infiltration. In addition, IL-18 neutralizing antibodies selectively abated ISO-induced chemokines, proinflammatory cytokines and adhesion molecules but not growth factors. Moreover, blocking IL-18 early after ISO treatment effectively attenuated cardiac inflammation and fibrosis. Conclusion: Inflammasome-dependent activation of IL-18 within the myocardium upon acute ß-AR over-activation triggers cytokine cascades, macrophage infiltration and pathological cardiac remodelling. Blocking IL-18 at the early stage of ß-AR insult can successfully prevent inflammatory responses and cardiac injuries.

Exacerbated cardiac fibrosis induced by ß-adrenergic activation in old mice due to decreased AMPK activity.

Senescent hearts exhibit defective responses to ß-adrenergic receptor (ß-AR) over-activation upon stress, leading to more severe pathological cardiac remodelling. However, the underlying mechanisms remain unclear. Here, we investigated the role of adenosine monophosphate-activated protein kinase (AMPK) in protecting against ageing-associated cardiac remodelling in mice upon ß-AR over-activation. 10-week-old (young) and 18-month-old (old) mice were subcutaneously injected with the ß-AR agonist isoproterenol (ISO; 5 mg/kg). More extensive cardiac fibrosis was found in old mice upon ISO exposure than in young mice. Meanwhile, ISO treatment decreased AMPK activity and increased ß-arrestin 1, but not ß-arrestin 2, expression, and the effects of ISO on AMPK and ß-arrestin 1 were greater in old mice than in young mice. Similarly, young AMPKα2-knockout (KO) mice showed more extensive cardiac fibrosis upon ISO exposure than that was observed in age-matched wild-type (WT) littermates. The extent of cardiac fibrosis in WT old mice was similar to that in young KO mice. Additionally, AMPK activities were decreased and ß-arrestin 1 expression increased in KO mice. In contrast, the AMPK activator metformin decreased ß-arrestin 1 expression and attenuated cardiac fibrosis in both young and old mice upon ISO exposure. In conclusion, more severe cardiac fibrosis is induced by ISO in old mice than in young mice. A decrease in AMPK activity, which further increases ß-arrestin 1 expression, is the central mechanism underlying the ageing-related cardiac fibrosis induced by ISO. The AMPK activator metformin is a promising therapeutic agent for treating ageing-related cardiac remodelling upon ß-AR over-activation.

Grb2-associated binder 1 is essential for cardioprotection against ischemia/reperfusion injury.

We have shown recently that endothelial Grb-2-associated binder 1 (Gab1), an intracellular scaffolding adaptor, has a protective effect against limb ischemia via mediating angiogenic signaling pathways. However, the role of Gab1 in cardiac ischemia/reperfusion (I/R) injury remains unknown. In this study, we show that Gab1 is required for cardioprotection against I/R injury. I/R injury led to remarkable phosphorylation of Gab1 in cardiomyocytes. Compared with controls, the mice with cardiomyocyte-specific deletion of Gab1 gene (CGKO mice) exhibited an increase in infarct size and a decrease in cardiac function after I/R injury. Consistently, in hearts of CGKO mice subjected to I/R, the activation of caspase 3 and myocardial apoptosis was markedly enhanced whereas the activation of protein kinase B (Akt) and mitogen-activated protein kinase (MAPK), which are critical for cardiomyocyte survival, was attenuated. Oxidative stress is regarded as a major contributor to myocardial I/R injury. To examine the role of Gab1 in oxidative stress directly, isolated adult cardiomyocytes were subject to oxidant hydrogen peroxide and the cardioprotective effects of Gab1 were confirmed. Furthermore, we found that the phosphorylation of Gab1 and Gab1-mediated activation of Akt and MAPK by oxidative stress was suppressed by ErbB receptor and Src kinase inhibitors, accompanied by an increase in apoptotic cell death. In conclusion, our results suggest that Gab1 is essential for cardioprotection against I/R oxidative injury via mediating survival signaling.

Ginsenoside RH4 inhibits Ang II-induced myocardial remodeling by interfering with NFIL3.

Ventricular remodeling refers to the structural and functional changes of the heart under various stimuli or disease influences and may also be accompanied by myocardial fibrosis, where an excessive amount of fibrous tissue appears in the myocardial tissue, affecting the heart's normal contraction and relaxation. Hypertension is posing the potential risk of causing myocardial injury and remodeling. The significance of the renin-angiotensin-aldosterone system (RAAS) in myocardial remodeling cannot be overlooked. Drug targeting of RAAS can effectively lower blood pressure and reduce left ventricular mass. Studies have shown that ginsenoside Rh4 can inhibit oxidative stress and inflammatory responses. In this study, a myocardial remodeling model was established using angiotensin (Ang) II, and the inhibitory effect of RH4 on myocardial hypertrophy and remodeling induced by Ang II was investigated using pathological staining and quantitative polymerase chain reaction (qPCR). Immunofluorescence and qPCR demonstrated that Rh4 causes myocardial hypertrophy and the generation of reactive oxygen species (ROS) in vitro. The Rh4 target was identified using transcriptomics. The findings indicated that RH4 could inhibit myocardial hypertrophy, inflammatory fibrosis, and oxidative stress induced by Ang II, suggesting potential cardiovascular protection effects. In vitro experiments have shown that Rh4 inhibits myocardial hypertrophy. Transcriptomics revealed that nuclear factor interleukin-3 (NFIL3) is a downstream regulator of Rh4. By constructing AAV9-NFIL3 and injecting it into mice, it was found that NFIL3 overexpression interfered with anti-Ang II-induced myocardial remodeling of Rh4. These results indicate that Rh4 demonstrates potential therapeutic effects on myocardial hypertrophy and fibrosis.

Ginaton reduces M1-polarized macrophages in hypertensive cardiac remodeling via NF-κB signaling.

Introduction: Macrophages play a critical role in cardiac remodeling, and dysregulated macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypes promotes excessive inflammation and cardiac damage. Ginaton is a natural extract extracted from Ginkgo biloba. Because of its anti-inflammatory properties, it has long been used to treat a variety of diseases. However, the role of Ginaton in modulating the diverse macrophage functional phenotypes brought on by Ang II-induced hypertension and cardiac remodeling is unknown. Methods: In the present study, we fed C57BL/6J mice in the age of eight weeks with Ginaton (300 mg/kg/day) or PBS control, and then injected Ang II (1000 ng/kg/min) or saline for 14 days to investigate the specific efficacy of Ginaton. Systolic blood pressure was recorded, cardiac function was detected by echocardiography, and pathological changes in cardiac tissue were assessed by histological staining. Different functional phenotypes of the macrophages were assessed by immunostaining. The mRNA expression of genes was assessed by qPCR analysis. Protein levels were detected by immunoblotting. Results: Our results showed that Ang II infusion significantly enhanced the activation and infiltration of macrophages with hypertension, cardiac insufficiency, myocardial hypertrophy, fibrosis and M1 phenotype macrophages compared with the saline group. Instead, Ginaton attenuated these effects. In addition, in vitro experiments showed that Ginaton inhibited Ang II-induced activation, adhesion and migration of M1 phenotype macrophages. Conclusion: Our study showed that Ginaton treatment inhibits Ang II-induced M1 phenotype macrophage activation, macrophage adhesion, and mitigation, as well as the inflammatory response leading to impaired and dysfunctional hypertension and cardiac remodeling. Gianton may be a powerful treatment for heart disease.

The relationship between geometry and hemodynamics of the stenotic carotid artery based on computational fluid dynamics.

OBJECTIVE: The purpose of this work was to investigate the relationship between the geometric factors and the hemodynamics of the stenotic carotid artery. METHODS: We retrospectively reviewed data of patients with carotid stenosis (40%-95%). The Navier-Stokes equations were solved using ANSYS CFX 18.0. Correlation analysis was based on Spearman's test. Geometric variables (p < 0.1 in the univariate analysis) were entered into the logistical regression. A receiver-operating characteristics analysis was used to detect hemodynamically significant lesions. RESULTS: 81 patients (96 arteries) were evaluated. The logistic regression analysis revealed that the translesional pressure ratio was significantly correlated with the stenosis degree (OR = 1.147, p < 0.001) and the angle between internal carotid artery and external carotid artery (angle γ) (OR = 0.933, p = 0.01). The translesional wall shear stress ratio was significantly correlated with stenosis degree (OR = 1.094, p < 0.001), lesion length (OR = 0.873, p = 0.01), lumen area of internal carotid artery (OR = 0.867, p = 0.002), and lumen area of common carotid artery (OR = 1.058, p = 0.01). For predicting low translesional pressure ratio, the AUC was 0.71 (p < 0.001) for angle γ, and was 0.87 (p < 0.001) for stenosis degree. For predicting high translesional wall shear stress ratio, the AUC was 0.62 (p = 0.04) for lumen area of internal carotid artery, and was 0.77 (p < 0.001) for stenosis degree. CONCLUSIONS: Apart from stenosis degree, other geometric characteristics of lesions may also have an influence on hemodynamics of the stenotic carotid artery.

Multiple telescoping flow diverter technique in endovascular treatment of a vertebrobasilar dissecting aneurysm: case report.

A 64-year-old man presented with headache and dizziness. A vertebrobasilar dissecting aneurysm was identified via computed tomography angiography and high resolution magnetic resonance imaging. Perioperatively, standard oral dual antiplatelet drugs were given. Two flow diverters were telespcoped for endovascular treatment of the aneurysm. Postoperatively, there were no signs of cerebral infarction and no new symptoms. At the 6-month follow-up, digital subtraction angiography showed that the aneurysm was almost completely occluded, with no other complications. This case serves as a reference for using the multiple telescoping flow diverter technique to treat vertebrobasilar dissecting aneurysm.

Hyperhomocysteinaemia Promotes Doxorubicin-Induced Cardiotoxicity in Mice.

Doxorubicin, a widely used chemotherapeutic drug in clinical oncology, causes a series of cardiac side effects referred to as doxorubicin-induced cardiotoxicity. Hyperhomocysteinaemia is an independent risk factor for multiple cardiovascular diseases. However, whether hyperhomocysteinaemia contributes to doxorubicin-induced cardiotoxicity is currently unknown. In this study, we explored the pathogenic effects of hyperhomocysteinaemia induced by dietary methionine supplementation (2% wt/wt in rodent chow) in a mouse model of doxorubicin-induced cardiotoxicity. Our data showed that methionine supplementation doubled serum homocysteine levels, inducing mild hyperhomocysteinaemia. Doxorubicin at a cumulative dosage of 25 mg/kg body weight led to significant weight loss and severe cardiac dysfunction, which were further exacerbated by methionine-induced mild hyperhomocysteinaemia. Doxorubicin-induced cardiac atrophy, cytoplasmic vacuolisation, myofibrillar disarray and loss, as well as cardiac fibrosis, were also exacerbated by methionine-induced mild hyperhomocysteinaemia. Additional folic acid supplementation (0.006% wt/wt) prevented methionine-induced hyperhomocysteinaemia and inhibited hyperhomocysteinaemia-aggravated cardiac dysfunction and cardiomyopathy. In particular, hyperhomocysteinaemia increased both serum and cardiac oxidative stress, which could all be inhibited by folic acid supplementation. Therefore, we demonstrated for the first time that hyperhomocysteinaemia could exacerbate doxorubicin-induced cardiotoxicity in mice, and the pathogenic effects of hyperhomocysteinaemia might at least partially correlate with increased oxidative stress and could be prevented by folic acid supplementation. Our study provides preliminary experimental evidence for the assessment of hyperhomocysteinaemia as a potential risk factor for chemotherapy-induced cardiotoxicity in cancer patients.

Severe hypertriglyceridemia caused by Gpihbp1 deficiency facilitates vascular remodeling through increasing endothelial activation and oxidative stress.

Hypertriglyceridemia (HTG) is an independent risk factor for atherosclerosis. However, its impact on non-atherosclerotic cardiovascular diseases remains largely unknown. Glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1 (GPIHBP1) is essential for the hydrolysis of circulating triglycerides and loss of functional GPIHBP1 causes severe HTG. In this study, we used Gpihbp1 knockout (GKO) mice to investigate the potential effects of HTG on non-atherosclerotic vascular remodeling. We compared the aortic morphology and gene expressions between three-month-old and ten-month-old GKO mice and their age-matched wild-type controls. We also conducted similar comparisons between GKO mice and wild-type controls in an angiotensin II (AngII)-induced vascular remodeling model. Our data showed that the intima-media wall of ten-month-old GKO mice but not three-month-olds was significantly thickened compared to wild-type controls. Moreover, ten-month-old GKO mice but not three-month-olds had increased aortic macrophage infiltration and perivascular fibrosis, along with increased endothelial activation and oxidative stress. Similarly, the AngII-induced vascular remodeling, as well as endothelial activation and oxidative stress, were also exacerbated in the GKO mice compared to wild-type controls. In conclusion, we demonstrated that severe HTG caused by Gpihbp1 deficiency could facilitate the onset and progression of non-atherosclerotic vascular remodeling through endothelial activation and oxidative stress in mice.

Low-Dose Gallic Acid Administration Does Not Improve Diet-Induced Metabolic Disorders and Atherosclerosis in Apoe Knockout Mice.

Diets rich in polyphenols are known to be beneficial for cardiovascular health. Gallic acid (GA) is a plant-derived triphenolic chemical with multiple cardio-protective properties, such as antiobesity, anti-inflammation, and antioxidation. However, whether GA could protect against atherosclerotic cardiovascular diseases is still not defined. Here, we investigated the effects of low-dose GA administration on diet-induced metabolic disorders and atherosclerosis in the atherosclerosis-prone apolipoprotein E (Apoe) knockout mice fed on a high-fat Western-type diet (WTD) for 8 weeks. Our data showed that GA administration by oral gavage at a daily dosage of 20 mg/kg body weight did not significantly ameliorate WTD-induced hyperlipidemia, hepatosteatosis, adipogenesis, or insulin resistance; furthermore, GA administration did not significantly ameliorate WTD-induced atherosclerosis. In conclusion, our data demonstrate that low-dose GA administration does not elicit significant health effect on diet-induced metabolic disorders or atherosclerosis in the Apoe knockout mice. Whether GA could be beneficial for atherosclerotic cardiovascular diseases therefore needs further exploration.

Hyperhomocysteinemia Promotes Cardiac Hypertrophy in Hypertension.

Hyperhomocysteinemia (HHcy) is positively linked with several cardiovascular diseases; however, its role and underlying mechanisms in pathological cardiac hypertrophy are still unclear. Here, we focused on the effects and underlying mechanisms of HHcy in hypertensive cardiac hypertrophy, one of the most common and typical types of pathological cardiac hypertrophy. By a retrospective analysis of the association between HHcy and cardiac hypertrophy in a hypertensive cohort, we found that the prevalence of HHcy was higher in patients with hypertrophy and significantly associated with the presence of cardiac hypertrophy after adjusting for other conventional risk factors. In mice, HHcy induced by a methionine (2% wt/wt) diet feeding significantly promoted cardiac hypertrophy as well as cardiac inflammation and fibrosis induced by 3-week angiotensin ІІ (AngІІ) infusion (1000 ng/kg/min), while folic acid (0.006% wt/wt) supplement corrected HHcy and attenuated AngII-stimulated cardiac phenotypes. Mechanistic studies further showed that homocysteine (Hcy) exacerbated AngII-stimulated expression of Calcineurin and nuclear factor of activated T cells (NFAT), which could be attenuated by folic acid both in mice and in neonatal rat cardiomyocytes. Moreover, treatment with cyclosporin A, an inhibitor of Calcineurin, blocked Hcy-stimulated Calcineurin-NFAT signaling and hypertrophy in neonatal rat cardiomyocytes. In conclusion, our study indicates that HHcy promotes cardiac hypertrophy in hypertension, and Calcineurin-NFAT pathway might be involved in the pro-hypertrophic effect of Hcy.

Quantitative Assessment of Changes in Hemodynamics After Obliteration of Large Intracranial Carotid Aneurysms Using Computational Fluid Dynamics.

Background: It was speculated that the alteration of the geometry of the artery might lead to hemodynamic changes of distal arteries. This study was to investigate the hemodynamic changes of distal arterial trees, and to identify the factors accounting for hyperperfusion after the obliteration of large intracranial aneurysms. Methods: We retrospectively reviewed data of 12 patients with intracranial carotid aneurysms. Parametric models with intracranial carotid aneurysm were created. Patient-specific geometries were generated by three-dimensional rotational angiography. To mimic the arterial geometries after complete obliteration of the aneurysms, the aneurysms were virtually removed. The Navier-Stokes equations were solved using ANSYS CFX 14. The average wall shear stress, pressure and flow velocity were measured. Results: Pressure ratio values were significantly higher in A1 segments, M1 segments, and M2 + M3 segments after obliteration of the aneurysms (p = 0.048 in A1 segments, p = 0.017 in M1 segments, p = 0.001 in M2 + M3 segments). Velocity ratio values were significantly higher in M1 segments and M2 + M3 segments after obliteration of the aneurysms (p = 0.047 in M1 segments, p = 0.046 in M2 + M3 segments). The percentage of pressure ratio increase after obliteration of aneurysms was significantly correlated with aneurysmal angle (r = 0.739, p = 0.006 for M2 + M3). Conclusions: The pressure and flow velocity of distal arterial trees became higher after obliteration of aneurysms. The angle between the aneurysm and the parent artery was the factor accounting for pressure increase after treatment.

Lipoprotein Glomerulopathy-Like Lesions in Atherosclerotic Mice Defected With HDL Receptor SR-B1.

High-density lipoprotein (HDL) homeostasis is important in maintaining both cardiovascular and renal health. Scavenger receptor class B type 1 (SR-B1), the major HDL receptor in mammals, plays a crucial role in reverse cholesterol transport and HDL metabolism. Evidence from mouse study has well demonstrated that HDL disorders caused by Srb1 inactivation accelerate atherosclerosis and even induce lethal cardiovascular diseases. However, the renal consequences of Srb1 dysfunction are still unknown. Here we explored this issue in both Srb1 knockout (Srb1-/-) mice and atherosclerotic low-density lipoprotein receptor knockout (Ldlr-/-) mice with Srb1 deletion. Our data showed that no apparent renal damage was observed in 5-month-old Srb1-/- mice fed on standard rodent chow diet as well as Srb1-/- mice fed on a high-fat diet (HFD) for 12 weeks. However, 5-month-old Srb1/Ldlr-/- mice fed on rodent chow had increased urinary albumin excretion and developed spontaneous intraglomerular Oil-red O (ORO)-positive lipoprotein deposition that is similar to lesions observed in human lipoprotein glomerulopathy (LPG). HFD feeding accelerated LPG-like lesions in Srb1/Ldlr-/- mice, inducing severe proteinuria and significantly promoting intraglomerular ORO-positive lipoprotein deposition. Interestingly, probucol reversed HFD-induced HDL disorders and almost fully abrogated LPG-like lesions in Srb1/Ldlr-/- mice. In conclusion, the present study demonstrates that SR-B1 dysfunction leads to LPG-like lesions in atherosclerotic mice, which could be rescued by probucol. SR-B1 loss-of-function mutant carriers therefore might be susceptible to developing metabolic nephropathy in addition to cardiovascular diseases, and probucol might be a potential therapeutics.

Radiomics Analysis Based on Contrast-Enhanced MRI for Prediction of Therapeutic Response to Transarterial Chemoembolization in Hepatocellular Carcinoma.

PURPOSE: To investigate the role of contrast-enhanced magnetic resonance imaging (CE-MRI) radiomics for pretherapeutic prediction of the response to transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). METHODS: One hundred and twenty-two HCC patients (objective response, n = 63; non-response, n = 59) who received CE-MRI examination before initial TACE were retrospectively recruited and randomly divided into a training cohort (n = 85) and a validation cohort (n = 37). All HCCs were manually segmented on arterial, venous and delayed phases of CE-MRI, and total 2367 radiomics features were extracted. Radiomics models were constructed based on each phase and their combination using logistic regression algorithm. A clinical-radiological model was built based on independent risk factors identified by univariate and multivariate logistic regression analyses. A combined model incorporating the radiomics score and selected clinical-radiological predictors was constructed, and the combined model was presented as a nomogram. Prediction models were evaluated by receiver operating characteristic curves, calibration curves, and decision curve analysis. RESULTS: Among all radiomics models, the three-phase radiomics model exhibited better performance in the training cohort with an area under the curve (AUC) of 0.838 (95% confidence interval (CI), 0.753 - 0.922), which was verified in the validation cohort (AUC, 0.833; 95% CI, 0.691 - 0.975). The combined model that integrated the three-phase radiomics score and clinical-radiological risk factors (total bilirubin, tumor shape, and tumor encapsulation) showed excellent calibration and predictive capability in the training and validation cohorts with AUCs of 0.878 (95% CI, 0.806 - 0.950) and 0.833 (95% CI, 0.687 - 0.979), respectively, and showed better predictive ability (P = 0.003) compared with the clinical-radiological model (AUC, 0.744; 95% CI, 0.642 - 0.846) in the training cohort. A nomogram based on the combined model achieved good clinical utility in predicting the treatment efficacy of TACE. CONCLUSION: CE-MRI radiomics analysis may serve as a promising and noninvasive tool to predict therapeutic response to TACE in HCC, which will facilitate the individualized follow-up and further therapeutic strategies guidance in HCC patients.

Quercetin Dihydrate inhibition of cardiac fibrosis induced by angiotensin II in vivo and in vitro.

Cardiac fibroblasts play a key role in the process of myocardial remodeling and myocardial fibrosis, which will eventually lead to heart failure. Quercetin Dihydrate has been studied in cardiovascular disease, but its effect on myocardial fibrosis is not clear. Here, cardiac remodeling was induced by infusion of Ang II (1000 ng/kg/min) for 2 weeks in mice. Quercetin Dihydrate was injected intraperitoneally for 25 mM/kg body weight (BW) once two days. We found that Quercetin Dihydrate significantly reduced cardiac contractile function, fibrosis, inflammation and myocardial hypertrophy induced by Ang II. Quercetin Dihydrate could inhibit the expression of Collagen I and Collagen III, which are the markers of fibroblast differentiation. We also verified the inhibitory effect of Quercetin Dihydrate on the proliferation and differentiation of fibroblasts induced by angiotensin II in vitro. Our results show that quercetin dihydrate plays a key role in the progression of myocardial fibrosis and suggests that Quercetin Dihydrate may be a promising drug for the treatment of myocardial fibrosis.

Platelets Promote Ang II (Angiotensin II)-Induced Atrial Fibrillation by Releasing TGF-ß1 (Transforming Growth Factor-ß1) and Interacting With Fibroblasts.

Hypertension is a risk factor of atrial fibrillation (AF), and a certain number of patients with hypertension were found with an enlarged left atrium. Platelet activation is found in patients with hypertension or pressure overload/Ang II (angiotensin II)-induced hypertensive animal models and contribute to ventricular fibrosis. Whether hypertension-induced atrial fibrosis is mediated by platelets remains unknown. Our previous experimental data showed that platelet-derived TGF-ß1 (transforming growth factor-ß1) was reduced in patients with hypertensive AF. The present study is to investigate whether platelet-derived TGF-ß1 promotes Ang II-induced atrial fibrosis and AF. Platelet activation and atrial platelet accumulation were measured in sinus rhythm controls, normotensive AF, and patients with hypertensive AF. Ang II (1500 ng/kg per minute, 3 weeks) infused mice with pharmacological (clopidogrel) and genetic platelet inhibition (TGF-ß1 deletion in platelets) were used. Platelet activation, atrial structural remodeling, atrial electrical transmission, AF inducibility, inflammation, and fibrosis were measured in mice. We found that circulating platelets were activated in patients with hypertensive AF. A large amount of platelet was accumulated in the atriums of patients with hypertensive AF. Both clopidogrel treatment and platelet-specific deletion of TGF-ß1 attenuated Ang II-induced structural remodeling, atrial electrical transmission, AF inducibility, as well as atrial inflammation and fibrosis than mice without interventions. Furthermore, clopidogrel blocked atrial platelet accumulation and platelet-fibroblast conjugation. Platelets promoted atrial fibroblast differentiation in cell culture. Profibrotic actions of platelets are largely via activation of atrial fibroblasts by releasing TGF-ß1 and inducing platelet-fibroblast conjugation, and platelet inhibition is sufficient to inhibit atrial fibrosis and AF inducibility.

Deficiency of LMP10 Attenuates Diet-Induced Atherosclerosis by Inhibiting Macrophage Polarization and Inflammation in Apolipoprotein E Deficient Mice.

Macrophage polarization and inflammation are key factors for the onset and progression of atherosclerosis. The immunoproteasome complex consists of three inducible catalytic subunits (LMP2, LMP10, and LMP7) that play a critical role in the regulation of these risk factors. We recently demonstrated that the LMP7 subunit promotes diet-induced atherosclerosis via inhibition of MERTK-mediated efferocytosis. Here, we explored the role of another subunit of LMP10 in the disease process, using ApoE knockout (ko) mice fed on an atherogenic diet (ATD) containing 0.5% cholesterol and 20% fat for 8 weeks as an in vivo atherosclerosis model. We observed that ATD significantly upregulated LMP10 expression in aortic lesions, which were primarily co-localized with plaque macrophages. Conversely, deletion of LMP10 markedly attenuated atherosclerotic lesion area, CD68+ macrophage accumulation, and necrotic core expansion in the plaques, but did not change plasma metabolic parameters, lesional SM22α+ smooth muscle cells, or collagen content. Myeloid-specific deletion of LMP10 by bone marrow transplantation resulted in similar phenotypes. Furthermore, deletion of LMP10 remarkably reduced aortic macrophage infiltration and increased M2/M1 ratio, accompanied by decreased expression of pro-inflammatory M1 cytokines (MCP-1, IL-1, and IL-6) and increased expression of anti-inflammatory M2 cytokines (IL-4 and IL-10). In addition, we confirmed in cultured macrophages that LMP10 deletion blunted macrophage polarization and inflammation during ox-LDL-induced foam cell formation in vitro, which was associated with decreased IκBα degradation and NF-κB activation. Our results show that the immunoproteasome subunit LMP10 promoted diet-induced atherosclerosis in ApoE ko mice possibly through regulation of NF-κB-mediated macrophage polarization and inflammation. Targeting LMP10 may represent a new therapeutic approach for atherosclerosis.

Ginsenoside Rd contributes the attenuation of cardiac hypertrophy in vivo and in vitro.

Cardiac hypertrophy are the major health challenges in the whole world. Ginsenoside Rd is an important component of cell growth and tumorigenesis, but the role and mechanism of ginsenoside Rd in pressure overload induced cardiac dysfunction and remodeling are still not fully illuminated. Here, cardiac hypertrophic remodeling and dysfunction were induced by pressure overload in mice. Myocardial histology was detected by Masson's trichrome staining and hematoxylin-eosin staining (H&E). Western blot was used to detect protein levels of signal mediators. Cardiac function was evaluated by echocardiography, and qPCR analysis was used to detect mRNA expression of hypertrophy and fibrosis markers. Cardiomyocyte size was detected by Wheat germ agglutinin (WGA) staining. Dihydroethidine (DHE) staining was used to detect oxidative stress. We also detected the influence of Ginsenoside Rd on rat neonatal cardiac myocytes (NRCMs) treated by Phenylephrine (PE). Our results showed that Ginsenoside Rd significantly improved pressure overload induced contractile dysfunction, fibrosis, cardiac hypertrophy, inflammation and oxidative stress in mice. Moreover, protein levels of AKT, calcineurin A, ERK1/2 and TGF-ß1 were significantly decreased in the Ginsenoside Rd-treated hearts as compared to control. Ginsenoside Rd treated in cardiomyocytes inhibited PE-induced cardiomyocyte hypertrophy. These results revealed that ginsenoside Rd improved cardiac dysfunction and remodeling induced by pressure overload, which is related to the inhibition of a variety of signaling pathways.

Cerebral arterial air embolism after computed tomography-guided hook-wire localization of a pulmonary nodule: A case report.

RATIONALE: Cranial arterial air embolism is a rare but potentially fatal complication after computed tomography (CT)-guided pulmonary interventions. PATIENT CONCERNS: A 64-year-old man was diagnosed with a pulmonary nodule (diameter: approximately 1 cm) in the right lower lobe. The patient developed convulsions after CT-guided hook-wire localization. DIAGNOSIS: Cranial CT revealed arborizing/linearly distributed gas in the territory of the right middle cerebral artery. INTERVENTIONS: The patient was administered hyperbaric oxygen, antiplatelet aggregation therapy, and dehydration treatment. OUTCOMES: Clinical death occurred 55 hours after air embolism. LESSONS: Systemic air embolism is a serious complication of lung puncture. Clinicians should improve their understanding of this complication and remain vigilant against air embolism.