bluuebunny/crossref_metadata_2025 huggingface dataset:
Dapagliflozin protects Doxorubicin induced cardiotoxicity in patients with diabetes via suppressing ER stress
Authors: Wei-Ting C , Lin Y.W , Ho C.H , Chen Z.C
Published: November 2020

Objectives

Cancer patients with diabetes have an increasing risk of Doxorubicin (Dox)-induced cardiotoxicity. Despite previous studies reporting benefits of dapagliflozin on the cardiovascular system, it remains unknown whether dapagliflozin has a cardioprotective effect in cancer patients with diabetes receiving Dox therapy. The purpose of this study is to investigate the potentials of dapagliflozin in preventing Dox induced cardiotoxicity.

Methods

Using National Health Insurance Database, the incidence of heart failure of breast cancer patients with or without diabetes was investigated. Also, streptozotocin (STZ) induced diabetic rats were pretreated with oral dapagliflozin (10 mg/kg/day) for 6 weeks and received Dox (5 mg/kg/week) for 4 weeks via intraperitoneally injection. Sequential echocardiography was applied to assess the cardiac function. For in vitro analysis, H9C2 cardiomyocytes, cultured in high glucose (30 mM), were treated with dapagliflozin at 10 mM and subsequently exposed to Dox at 1 mM. The apoptosis and endoplasmic reticulum (ER) stress related protein expression were measured by immunohistochemistry and western blotting.

Results

Among the studied patients, those with diabetes have a higher risk of heart failure while patients prescribed with dapagliflozin lowered the risks. Correspondingly, dapagliflozin treatment effectively inhibited Dox-induced apoptosis and reactive oxygen species accumulation in cardiomyocytes. Also, the reduction of cardiac fibrosis as well as apoptosis in rats treated with dapagliflozin resulted in significantly improved cardiac function. Dapagliflozin also decreased the cardiac expression of Bax, cleaved caspase 3 and increased Bcl-2. Mechanistically, we showed that dapagliflozin significantly reduced ER stress-associated proteins including GRP78, PERK, eIF 2a, ATF-4, and CHOP.

Conclusions

Our study revealed for the first time that dapagliflozin mitigated Dox-induced cardiomyocyte apoptosis in diabetes via inhibiting ER stress. These results indicate that dapagliflozin could be useful in preventing cardiotoxicity in diabetic cancer patients receiving Dox treatment.

Funding Acknowledgement

Type of funding source: Private hospital(s). Main funding source(s): Chi-Mei Medical Center, Tainan, Taiwan
Genome-wide association study of patients with atrioventricular nodal reentry tachycardia
Authors: Andreasen L , Ahlberg G , Hartmann J , Paludan-Mueller C , Jensen H.K , Riahi S , Hansen J , Sandgaard N , Haunsoe S , Kanters J.K , Ellervik C , Bundgaard H , Svendsen J.H , Olesen M.S
Published: November 2020

Background

Supraventricular tachycardias (SVTs) originate from the atria or the area close to the AV node. AV nodal reentry tachycardia (AVNRT) is one of the tachyarrhytmias comprising the group of SVTs. The typical patient is female, young at disease onset, with a structurally normal heart. At present we do not know the etiology of AVNRT. We therefore hypothesized that AVNRT might be caused by changes in the DNA.

Methods

DNA from purified blood was obtained from patients with AVNRT verified by an invasive electrophysiological study. Patients were recruited from five ablation centers in Denmark and individuals from the general population of Denmark (the BEFUS cohort) served as controls. DNA was subjected to chip genotyping, imputation and analyses in a genome-wide association study (GWAS) setup.

Results

A GWAS on 1,143 AVNRT patients and 3,004 controls revealed one locus close to the gene MYH6 to reach genome-wide significance for association with AVNRT (P=4.8x10–8). MYH6 encodes the α-isoform of the protein myosin heavy chain important for the contractile units of the heart, the sarcomeres. The gene is predominantly expressed in the atria. Additional subthreshold loci located close to other plausible arrhythmia genes were identified.

Conclusion

We report the first genetic locus to be associated with AVNRT close to the sarcomere gene MYH6. This is, to our knowledge, the first gene ever associated with AVNRT.

Manhattan plot

Funding Acknowledgement

Type of funding source: Public hospital(s). Main funding source(s): Rigshospitalets Forskningspulje - 3 years PhD salary
Reverse use dependence of calcium sensitizer levosimendan on action potential duration shortening prevents ventricular arrhythmia during therapeutic hypothermia
Authors: Hsieh Y.C , Li C.H , Lin J.C , Weng C.J , Chien Y.S , Lin S.F , Huang J.L , Wu T.J
Published: November 2020

Background

Therapeutic hypothermia (TH) increases the risk of ventricular arrhythmia (VA) by prolonging action potential duration (APD) and steepening the APD restitution (APDR). The calcium sensitizer levosimendan, a medication for heart failure treatment, has been reported to shorten APD by enhancing ATP-sensitive K current and affect the APDR.

Purpose

We hypothesized that levosimendan might shorten the already prolonged APD particularly at long pacing cycle length (PCL), thus decreases the maximal slope of APDR, and prevent VA during TH.

Methods

Langendorff-perfused isolated rabbit hearts were subjected to 15-min TH (30°C) followed by 30-min treatment with levosimendan (0.5 μM, n=9) or vehicle (n=8). Using an optical mapping system, APD was evaluated by S1 pacing and APDR curve was plotted using APD70 versus diastolic interval. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 s at the shortest PCL that achieved 1:1 ventricular capture.

Results

The APD was shortened from 259±8 ms at TH to 241±18 ms after levosimendan infusion at long PCL of 400 ms (p=0.024). However, at short PCL of 280 ms, the APD was not changed before (194±19) and after (188±23) levosimendan during TH (p=0.61). Levosimendan decreases the maximal slope of APDR curve from 1.99±0.65 at TH to 1.41±0.32 after adding levosimendan (p=0.034). The VF inducibility was decreased by levosimendan from 39±30% at 30°C to 14±12% with levosimendan (p=0.023). In control hearts, the maximal slope of APDR (p=0.75) and VF inducibility (p=0.12) were not changed by vehicle during TH.

Conclusion

Levosimendan might protect the hearts against VA during TH by shortening APD at long PCL and flattening the APDR. Enhancing ATP-sensitive K current with levosimendan during TH might be a novel approach to prevent VA during TH.

Funding Acknowledgement

Type of funding source: None
Suppression of ventricular arrhythmia by mitochondrial calcium uptake via mitochondrial calcium uniporter in the ischemic heart failure mice
Authors: Hagiwara H , Watanabe M , Fujioka Y , Koya T , Nakao M , Takahashi Y , Kamada R , Ohba Y , Anzai T
Published: November 2020

Background

In heart failure (HF), diastolic calcium (Ca) leak from sarcoplasmic reticulum (SR) via ryanodine receptor (RyR) causes delayed after depolarization (DAD), leading ventricular arrhythmias (VAs). Recent study reported that Ca uptake into mitochondria via mitochondrial calcium uniporter (MCU) suppress Ca waves (CaWs) and DAD in catecholaminergic polymorphic ventricular tachycardia, in which diastolic Ca leak is thought to be a major cause of VAs as in HF. However, such anti-arrhythmic effect of mitochondrial Ca uptake via MCU remains unclear in HF.

Purpose

We sought to investigate whether mitochondrial Ca uptake via MCU decreases CAWs and VAs incidence in ischemic HF mice.

Methods

Ten-week-old male C57BL/6J mice were divided into 2 groups; sham operation mice (Sham) or HF mice (HF) in which myocardial infarction was induced by left coronary artery ligation. After 4–6 weeks, cardiomyocyte or mitochondria was isolated respectively from the myocardium of Sham and the non-infarct myocardium of HF. Influence of MCU activation on Ca dynamics, VA inducibility and left ventricular hemodynamics were evaluated using Kaemenpferol, a MCU activator. Intracellular Ca dynamics and mitochondrial Ca uptake were measured in isolated cardiomyocytes loaded with Fluo-4 AM on an epifluorescence microscopy and by estimating the extra-mitochondrial Ca reduction with Fluo-5N on a spectrofluoro-photometer, respectively. VAs was induced by programmed stimulation in the Langendorff perfused hearts. Left ventricular (LV) pressure was measured using a microtip transducer catheter. Finally, the effect of intravenous administration of Kaempferol (5mg/kg) on hemodynamic parameters was examined 30 minutes after administration in Sham and HF.

Results

HF mice showed left ventricular dysfunction, as well as the increased heart and lung weights compared to Sham. MCU protein expression in cardiomyocytes did not differ between Sham and HF. Kaempferol increased mitochondrial Ca uptake in the isolated mitochondria both in Sham and HF. The number of the diastolic CaWs was higher in HF compared to Sham. Such increased number of CaWs in HF was attenuated by 10 μM Kaempferol, which was, however, abolished by a MCU blocker Ruthenium Red. The incidence of induced VA was significantly higher in HF than Sham, which was suppressed by Kaempferol. In vivo measurements, intravenous administration of Kaempferol did not show significant changes in hemodynamic parameters in Sham and HF mice.

Conclusions

Mitochondrial Ca uptake via MCU suppresses CaWs and VAs, but did not change LV hemodynamics in HF. Whereas traditional antiarrhythmic drugs have limited use in heart failure patients, a novel strategy that promotes Ca uptake into mitochondria might be a new and safer option for treating VAs in HF.

Funding Acknowledgement

Type of funding source: None
The genetic architecture of left ventricular non-compaction reveals both substantial overlap with other cardiomyopathies and a distinct aetiology in a subset of cases
Authors: Walsh R , Mazzarotto F , Hawley M , Beltrami M , Beekman L , Boschi B , Girolami F , Roberts A , Cerbai E , Cook S , Ware J , Funke B , Olivotto I , Bezzina C , Barton P
Published: November 2020

Background

Left ventricular non-compaction (LVNC) is a condition characterised by trabeculations in the myocardial wall and is the subject of considerable conjecture as to whether it represents a distinct pathology or a secondary phenotype associated with other cardiac diseases, particularly cardiomyopathies.

Purpose

To investigate the genetic architecture of LVNC by identifying genes and variant classes robustly associated with disease and comparing these to other genetically characterised cardiomyopathies.

Methods

We performed rare variant association analysis using six different LVNC cohorts comprising 840 cases together with 125,748 gnomAD population controls and compared results to similar analyses with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) cases.

Results

We observed substantial overlap in genes and variant classes enriched in LVNC and DCM/HCM, indicating that in many cases LVNC belongs to a spectrum of more established cardiomyopathies, with non-compaction representing a phenotypic variation in patients with DCM- or HCM-causing variants. In contrast, five variant classes were uniquely enriched in LVNC cases, of which truncating variants in MYH7, ACTN2 and PRDM16 may represent a distinct LVNC aetiology. MYH7 truncating variants are generally considered as non-pathogenic but were detected in 2% of LVNC cases compared to 0.1% of controls, including a cluster of variants around a single splice region. Additionally, structural variants (exon deletions) in RYR2 and missense variants in the transmembrane region of HCN4 were enriched in LVNC cases, confirming prior reports regarding the association of these variant classes with combined LVNC and arrhythmia phenotypes.

Conclusions

We demonstrated that genetic association analysis can clarify the relationship between LVNC and established cardiomyopathies, highlighted substantial overlap with DCM/HCM but also identified variant classes associated with distinct LVNC and with joint LVNC/arrhythmia phenotypes. These results underline the complex genetic landscape of LVNC and inform how genetic testing in LVNC cases should be pursued and interpreted.

Cardiomyopathy rare variant frequencies

Funding Acknowledgement

Type of funding source: None
Pharmacological inhibition of C-C chemokine receptor 4 aggravates atherosclerosis through prevention of regulatory T cell recruitment to the lesions
Authors: Amin H , Sasaki N , Horibe S , Kawauchi S , Hirata K , Rikitake Y
Published: November 2020

Background

Regulatory T cells (Tregs) are demonstrated to play a protective role in the development of atherosclerosis. However, their sites of action in atherosclerosis remain unclear. Although C-C chemokine receptor 4 (CCR4) has been shown to contribute to the accumulation of Tregs in inflamed tissues and prevention of experimental autoimmune diseases, the role of CCR4 in Treg migration to atherosclerotic lesions and suppression of plaque formation remains unknown.

Methods and results

We intraperitoneally injected 8-week-old apolipoprotein E–deficient mice fed a normal diet with vehicle (n=9) or a 4-μg dose of a CCR4 antagonist (n=10) 3 times weekly for 8 weeks and evaluated atherosclerotic lesions at 16 weeks old. Administration of the CCR4 antagonist significantly aggravated atherosclerotic plaque formation (aortic sinus plaque area: 2.91±0.87×104 μm2 versus 5.41±0.98×104 μm2 in control vehicle-treated and CCR4 antagonist-treated mice, respectively; P<0.05), associated with increased accumulation of macrophages and CD4+T cells in the plaques. Flow cytometric analysis revealed a decrease in Foxp3+ Tregs in the para-aortic lymph nodes and thoracoabdominal aortas of CCR4 antagonist-treated mice, along with a tendency toward increase in CD44highCD62Lloweffector T cells in para-aortic lymph nodes, indicating CCR4-dependent migration of Tregs to atherosclerotic lesions and their possible atheroprotective role. We observed no changes in splenic Foxp3+ Tregs and effector T cells following CCR4 antagonist treatment. We also investigated the effect of CCR4 blockade on advanced atherosclerosis using LDL receptor–deficient mice fed a high-cholesterol diet. Although 8-week treatment with the CCR4 antagonist led to a decrease in Foxp3+ Tregs in the atherosclerotic lesions, atherosclerotic lesion formation was not significantly affected, suggesting that CCR4-dependent Treg accumulation in atherosclerotic lesions is not critical for prevention of advanced atherosclerosis.

Conclusions

Our findings indicate an important role for CCR4 in promotion of Treg recruitment into atherosclerotic lesions and subsequent prevention of early atherosclerosis and suggest CCR4 as a novel therapeutic target for atherosclerosis.

Funding Acknowledgement

Type of funding source: None
Cardiac fibroblasts acquire properties of matrifibrocytes in vitro and in mice with pressure overload-induced congestive heart failure
Authors: Herum K.M , Gilles G , Romaine A , Melleby A.O , Christensen G , McCulloch A.D , Brakebusch C.H
Published: November 2020

Introduction

Activation of cardiac fibroblasts (CFB) is a key step in development of fibrosis in the heart. It was recently shown that, in addition to the well-studied myofibroblast (myoFB) phenotype, activated cardiac fibroblasts can adopt a newly defined matrifibrocyte phenotype, characterized by expression of extracellular matrix (ECM) genes associated with bone, cartilage and tendon development. However, it is unknown whether matrifibrocytes exists in the pressure-overloaded fibrotic and failing heart, and whether substrate stiffness drives differentiation.

Hypothesis

Matrifibrocyte differentiation occurs in vitro during culturing of primary cardiac fibroblasts, and in vivo in response to left ventricular pressure overload.

Methods

Left ventricular pressure overload induced by o-ring aortic banding (ORAB) induced cardiac phenotypes of concentric hypertrophic remodelling and congestive heart failure. Primary CFB from adult mice were cultured on plastic or soft polyacrylamide hydrogels (4.5 kPa) for various times. mRNA expression of phenotypic markers were measured by RT-PCR. Presence of smooth muscle α-actin (SMA) fibers was determined by immunocytochemistry.

Results

ECM genes normally expressed in bone and cartilage (COMP, CILP-2, OPG and SCX) were upregulated in hypertrophic left ventricles of mice with congestive heart failure. The myoFB marker acta2 was increased 2 weeks after ORAB, returned to baseline at 4 weeks and increased again at 20 weeks when the left ventricle was dilating and failing, indicating that the myoFB phenotype is not permanent. In vitro, primary CFB upregulated bone/cartilage-associated ECM genes after 12 days of culturing on plastic. Acta2 mRNA and SMA protein levels peaked after 9 days in culture whereafter they declined, indicating a shift in phenotype. Culturing primary CFB on soft (4.5 kPa) hydrogels delayed, but did not prevent, myoFB differentiation while expression of bone/cartilage ECM genes was absent or low, indicating that high stiffness is a driver of the matrifibrocyte phenotype. Blockers of mechanotransduction, SB431542 (TGFβRI inhibitor), Y27623 (ROCK inhibitor) and cyclosporine A (calcineurin inhibitor), completely inhibited myoFB differentiation but upregulated several matrifibrocyte markers, indicating that distinct signaling pathways regulate myoFB and matrifibrocyte differentiation. Removing inhibitors re-induced myofibroblast markers in cells on plastic but not on soft gels consistent with high stiffness promoting myofibroblast differentiation.

Conclusion

Primary cardiac fibroblasts acquire characteristics of matrifibrocytes in vitro when cultured for long time on plastic and in vivo in left ventricles of mice with pressure overload-induced congestive heart failure.

Funding Acknowledgement

Type of funding source: Public grant(s) – EU funding. Main funding source(s): Marie Sklodowska-Curie Individual Fellowship
iPSC-derived endothelial cells reflect accelerated senescence and increased inflammatory response in a CVD-risk stratified manner
Authors: Straessler E.T , Kiamehr M , Aalto-Setala K , Kraenkel N.K , Landmesser U.L
Published: November 2020

Background

Cardiovascular disease (CVD) remains the leading cause of death worldwide and its multifactorial nature is recognized, with both an individual's genetic background and lifestyle strongly impacting on its course. On a molecular level, accelerated cellular aging and increased inflammation interact to drive the severity of the disease. We have used patient-derived induced pluripotent stem cells (iPSC) to investigate the impact of a patients' genetic background on (epi-)genetically determined functionality, telomere attrition and inflammatory response.

Purpose

The purpose of this study is to investigate differences on the cellular level between iPSC-derived endothelial cells from risk-stratified CAD patients (both ACS and stable CAD) in both functionality, inflammatory response and ageing rate.

Methods

iPSCs were generated from participants with similar lifestyle but different disease progression (healthy >65 y/o, stable CAD >65 y/o, ACS <65y/o) and differentiated into endothelial cells (iPS-EC). After quality control, iPS-EC were exposed to inflammatory stimulation via TNF-α under static and pro- vs. anti-atherogenic flow conditions (laminar vs. disturbed flow, high vs. low shear stress) and their gene and protein expression of adhesion molecules was assessed by qPCR and flow cytometry. Telomere length was determined by a qPCR-based assay in iPSC-ECs after four (p4) and eleven population doublings [KN1] (p11) in fully supplemented growth medium.

Results

ACS-iPS-ECs showed a significantly stronger upregulation of E-selectin in response to inflammatory stimulation with TNF-a than healthy-iPS-ECs on mRNA level (ACS: 532.1-fold±48.7 vs. healthy: 322.3-fold±55.7, p=0.02). Similarly, ICAM1 protein upregulation was stronger in ACS-iPS-ECs than in healthy iPSC-ECs as assessed by flow cytometry (ACS: 1.4-fold±0.01 vs. healthy: 1.1-fold±0.0007; p<0.001) whereas VCAM1 upregulation was weaker in ACS-iPS-ECs compared to healthy controls (ACS: 1.8-fold±0.3 vs. healthy: 4.2-fold±0.9, p<0.001). Telomere shortening from p4 to p11 was significantly stronger in ACS-iPS-ECs compared to healthy controls (ACS: 35%±10 vs. healthy: 10%±5, p<0.05).

Conclusion

The more pronounced upregulation of specific adhesion molecules (E-Selectin, ICAM-1, but not VCAM-1) in response to inflammatory stimulation together with a stronger telomere attrition in ACS-iPS-EC hints at cells entering faster into a senescent state.

Funding Acknowledgement

Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Research scholarship from the German Society of Cardiology. Allocated research funds from University hospital.
Loss of platelet BMP4 reduces vascular inflammation and ameliorates vascular remodelling after carotid wire injury
Authors: Zhou Q , Jank M , Von Niessen N , Olivier C.B , Schmitt H , Anto-Michel N , Hilgendorf I , Bode C , Moser M
Published: November 2020

Background

Bone morphogenic proteins (BMPs) are members of the TGFβ superfamily. They have distinct functions during hemostasis and play a central role in various pathologic conditions, including cardiovascular diseases. Recent findings demonstrate that BMPs are also expressed in platelets. However, their function is poorly understood. Here, we investigate the role of platelet BMP4 during vascular inflammation and vascular remodelling.

Methods

BMP4 floxed mice were crossed with PF4 Cre mice to generate platelet-specific deletion of BMP4 (BMP4Plt−/−). Intravital microscopy of mesenteric veins was performed to evaluate leukocyte adhesion upon stimulation with TNFα. Expression of adhesion molecules and chemokines were analysed by RT-PCR and Western Blot. P-selectin and platelet-leukocyte aggregates were evaluated using flow cytometry. For carotid wire injury, BMP4Plt−/− were further crossed with LDLr−/− mice (BMP4Plt−/−/LDLr−/−). At 8 weeks of age, BMP4Plt−/−/LDLr−/− mice and control littermates received a 2-week diet containing 15.8% wt/wt fat and 1.25% cholesterol. Carotid wire injury was performed at the age of 10 weeks. Re-endothelialisation and neointimal hyperplasia were evaluated.

Results

Platelet morphology and function did not differ between BMP4Plt−/− and control mice. Stimulation with TNFα resulted in increased rolling and adherence of leukocytes to the vessel wall which was reduced in BMP4Plt−/− mice (175±25 versus 50±7 rolling cells and 16±3 versus 7±2 adherent cells, respectively). Expression of P-selectin, adhesion molecules and the chemokines RANTES and PF-4 were reduced in BMP4Plt−/− mice. Platelet activation by thrombin was reduced in BMP4Plt−/− mice, resulting in diminished P-Selectin and JONA expression. Furthermore, monocyte infiltration and circulating leukocyte-platelet complexes were reduced in BMP4Plt−/− mice. Loss of platelet BMP4 prevented neointima formation after carotid wire injury (4.2x104±0.9x104μm2 versus 14.9x104±2.2x104μm2 in BMP4Plt−/−/LDLr−/− and control mice, respectively). Interestingly, endothelial regeneration after injury was decelerated in BMP4Plt−/− mice. This is further demonstrated in-vitro, where platelet BMP4 promoted endothelial cell proliferation and migration.

Conclusion

Platelet-BMP4 deficiency reduced vascular inflammation and ameliorated intima hyperplasia after wire injury. This is partly mediated by inhibition of platelet activation, reduced expression of adhesion molecules and inflammatory response. Our finding suggests that BMP4 is a promising target for the treatment of vascular inflammation and restenosis.

Funding Acknowledgement

Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Else-Kröner Fresenius Foundation; German Cardiac Society
SDPR/Cavin-2 loss inhibits monocyte adhesion to endothelial cells in abdominal aortic aneurysm via suppressing the expression of adhesion molecules
Authors: Sakamoto A , Ogata T , Nakanishi N , Higuchi Y , Tsuji Y , Tomita S , Matoba S
Published: November 2020

Background

Abdominal aortic aneurysm (AAA) is a common and life-threatening vascular disease. The initial phase of AAA progression is vascular inflammation. Inflammation sites present adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1). These molecules play a crucial role in recruiting inflammatory cells to endothelial cells through NF-κB signaling. Endothelial cells express serum deprivation response (SDPR)/Cavin-2 localized in caveolae on the cell membrane. Although Cavin-2 is involved in such as cell proliferation, migration, and signal transduction, the role of Cavin-2 in vascular inflammation in the development of AAA is still unclear.

Purpose

To assess the influence of Cavin-2 deficiency in AAA development and clarify the role of Cavin-2 in the regulation of inflammatory cell adhesion in endothelial cells.

Methods

CaCl2-induced AAAs were induced by the periaortic application of 0.5 M CaCl2 in male SDPR-knockout (KO) and wild-type (WT) mice at 8–10 weeks of age. Angiotensin II (Ang II)-induced AAAs were created by 4-week-subcutaneous drug infusion in male ApoE-KO and ApoE/Cavin-2-double KO (DKO) mice at 24 weeks of age. Inflammatory response and cell adhesion were evaluated using human aortic endothelial cells (HAECs) and human monocytes (THP-1 cells).

Results

Six weeks after CaCl2 treatment, Cavin-2 deficiency significantly attenuated the development of AAAs. Elastin degradation was markedly suppressed and F4/80-positive macrophages infiltration in aortic walls were decreased in Cavin-2-KO mice. Although Ang II infusion for 4 weeks formed AAAs in ApoE KO mice and ApoE/Cavin-2-DKO mice, ApoE/Cavin-2-DKO mice exhibited the suppression of AAA formation independently of blood pressure. Immunohistochemical staining showed VCAM-1 expression on endothelial cells was suppressed in ApoE/Cavin-2-DKO mice. Further, in vitro co-culture experiment, the number of THP-1 cells adhered to TNF-treated SDPR-knockdown HAECs was decreased compared with that to control HAECs. Moreover, mRNA expression of VCAM-1 and ICAM-1 was decreased in TNFα-treated SDPR-knockdown HAECSs. Protein expression of VCAM-1 was also suppressed in TNFα-treated SDPR-knockdown HAECSs. The activity of NF-κB p65, an upstream regulator of VCAM-1 and ICAM-1,tended to be suppressed in TNFα-treated SDPR-knockdown HAECs.

Conclusion

In this study, we revealed that SDPR/Cavin-2 loss attenuated AAA development with the suppression of elastin degradation and macrophage infiltration. Our findings suggest that SDPR/Cavin-2 in the endothelial cells regulates the expression of adhesion molecules via NF-κB signaling and promotes the adhesion and infiltration of inflammatory cells to the aortic wall.

Funding Acknowledgement

Type of funding source: None
Impaired DNA damage response promotes atherosclerosis by enhancing cellular senescence and proinflammatory activation
Authors: Sakai C , Ishida M.I , Tashiro S.T , Yoshizumi M.Y , Ishida T.I
Published: November 2020

Background

DNA damage likely contributes to the pathogenesis and progression of atherosclerosis. Chemotherapy, radiotherapy and some DNA damage response (DDR) syndromes are known to increase atherosclerosis. However, causative links between DNA damage and atherosclerosis are yet to be established.

Purpose

The aim of this study was to investigate the role of impaired DDR in atherosclerosis.

Methods and results

Ku80, a DNA repair protein, -deficient apolipoprotein E knockout mice (Ku80+/− ApoE−/−) and ApoE−/m- mice were fed on high-fat diet for 4 weeks, and then oil red O staining was performed on their isolated aortas. Plaque area was significantly increased in Ku80+/− ApoE−/− mice. Immunohistochemical analysis of lesions from Ku80+/− ApoE−/− mice revealed enhanced accumulation of DNA double-strand breaks (DSBs). Similar results were obtained from Ku80+/− ApoE−/− mice fed on high-fat diet for 2 weeks which was considered as the early stages of atherosclerosis. mRNA levels of inflammatory cytokines such as IL-6 and MCP-1 in the aorta were significantly elevated in Ku80+/− ApoE−/− mice compared with those of ApoE−/− mice. To investigate whether impaired DDR is associated with the increased expression of inflammatory cytokines, vascular smooth muscle cells were isolated from Ku80 WT and Ku80+/− mice and subjected to quantitative RT-PCR analysis. mRNA levels of IL-6 and MCP-1 were significantly elevated in Ku80+/− cells. In addition, IκBα protein expression was significantly decreased in Ku80+/− cells, which suggested enhanced NF-κB activation in those cells. Immunofluorescent analysis revealed accumulation of DSBs and persistent DDR in Ku80+/− cells. In addition, elevated p16 mRNA level and senescence-associated β-gal activity were observed in Ku80+/− cells.

Conclusion

These results suggested that impaired DDR promoted atherosclerosis partly through cellular senescence and enhanced proinflammatory activation. Therefore, therapies targeting enhancing DDR may be beneficial in the prevention of DNA damage-induced atherosclerosis.

Funding Acknowledgement

Type of funding source: Public Institution(s). Main funding source(s): KAKENHI
Different tryptophan-kynurenine metabolism profiles in human pulmonary arterial hypertension and animal models of pulmonary hypertension
Authors: Cai Z , Klein T , Tu L , Geenen L.W , Tian S , Van Der Ley C , Van Faassen M , Kema I , Van Den Bosch A.E , De Rijke J.B , Reiss I.K.M , Duncker D.J , Boomars K.A , Guignabert C , Merkus D
Published: November 2020

Background

De novo NAD+ synthesis through the tryptophan-kynurenine (TK) metabolism was recognized as an important pathway in improving mitochondrial function and survival of injury or apoptotic cells, which are key processes involved in the pathogenesis of pulmonary arterial hypertension (PAH). Although abnormal TK metabolism has been reported in human PAH, the difference between human and animal models of pulmonary hypertension (PH) are currently unknown.

Objective

Determine and compare TK metabolism profiles in plasma from human PAH and 3 animal models of PH.

Methods

Human plasma was collected from treatment naïve patients with PAH (n=43) and healthy controls (n=111). Animal plasma was collected from 3 animal models of PH and corresponding controls, including monocrotaline (MCT) induced PH in rat (n=7, control n=6), Sugen + hypoxia (SuHx) induced PH in rat (n=5, control n=6), and pulmonary vein banding (PVB) induced PH in swine (n=7, control n=6). TK metabolites were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results

TK metabolism was altered in the plasma from of PAH compared to healthy controls (Figure 1A). Lower tryptophan (0.8 fold vs Control, p<0.0001), maintained 3-hydroxyanthranilic acid, and higher kynurenine, 3-hydroxykynurenine, anthranilic acid, and quinolinic acid (1.5, 2.6, 2.0, 2.6 fold vs Control, respectively, p all<0.0001) were seen in the plasma from human PAH. In the rat SuHx-PH model, kynurenine (0.7 fold, p<0.01) and quinolinic acid (0.5 fold, p<0.001) were lower, while 3-hydroxyanthranilic acid (4.3 fold, p<0.001) was higher in PH compared to control (Figure 1B). However, the TK metabolism was unaltered in MCT-PH model in rat (Figure 1C), and PVB-PH model in swine (Figure 1D).

Conclusions

TK metabolism was altered in the plasma from human PAH. The TK metabolism profiles were different among 3 animal models of PH, but did not mimic the profile in human PAH. Further research is required to determine the mechanism(s) behind the abnormal TK metabolism in human PAH as well as whether these mechanisms relate to disease onset or progression.

Figure 1

Funding Acknowledgement

Type of funding source: Foundation. Main funding source(s): This work was supported by the China Scholarship Council (201606230252) as well as the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-11, RECONNECT), and German Center for Cardiovascular Research (DZHK81Z0600207). Instrumentation support was received from AB Sciex, ltd. for LC-MS/MS analyses performed in this study.
Ponatinib induces vascular toxicity through the Notch-1 signaling pathway
Authors: Madonna R , Pieragostino D , Cufaro M , Doria V , Del Boccio P , Deidda M , Pierdomenico S , Cadeddu Dessalvi C , De Caterina R , Mercuro G
Published: November 2020

Background

Ponatinib, a third-generation tyrosine kinase inhibitor (TKI), is the only approved TKI that is effective against T315I mutations in patients with chronic myeloid leukemia (CML). Specific activation of Notch signaling in CML cells by ponatinib can be considered as the “on-target effect” on the tumor and represents a therapeutic approach for CML. Nevertheless, ponatinib-induced vascular toxicity remains a serious concern, with underlying mechanisms poorly understood.

Aims

We aimed at determining mechanisms of ponatinib-induced vascular toxicity, defining associated signaling pathways and identifying potential rescue strategies.

Methods and results

We exposed human umbilical endothelial cells (HUVECs) to ponatinib or vehicle in the presence or absence of the neutralizing factor anti-Notch-1 antibody for exposure times of 0–72 hours. Label-free proteomics and network analysis showed that protein cargo of HUVECs treated with ponatinib triggered apoptosis, and inhibited vasculature development (Fig. 1). We validated the proteomic data showing the inhibition of matrigel tube formation, an upregulation of cleaved caspase-3 and a downregulation of phosphorylated AKT and phosphorylated eNOS. We delineated the signaling of ponatinib-induced vascular toxicity demonstrating that ponatinib inhibits endothelial survival, reduces angiogenesis and induces endothelial senescence and apoptosis via Notch-1 pathway.

Conclusion

Ponatinib induced endothelial toxicity in vitro. Hyperactivation of Notch-1 in the vessels can lead to abnormal vascular development and vascular dysfunction. By hyperactivating Notch-1 in the vessels, ponatinib exerts an “on-target off turmor effect”, which leads to deleterious effects and may explain the drug's vasculotoxicity. Selective blockade of Notch-1 prevented ponatinib-induced vascular toxicity.

Figure 1

Funding Acknowledgement

Type of funding source: None
A case report on the successful interventional treatment of a rare cause of left heart failure in a 69-year-old woman
Authors: Podnar Tomaz , Plank Fabian , Müller Silvana , Mair Johannes
Published: November 2020

Background 

Dyspnoea is very common in elderly patients and can be caused by a variety of different diseases. However, the initial diagnosis of patent ductus arteriosus (PDA) as a cause of left heart failure is very rare in this patient population.

Case summary 

A 69-year-old physically active woman with known hypertension presented with worsening exertional dyspnoea. Echocardiography showed a dilated left ventricle with moderately reduced left ventricular ejection fraction, and evidence for PDA. The PDA was confirmed by computed tomography angiography and successfully closed by implantation of an Amplatzer PDA occluder II 06-06 mm. As a result, the heart failure symptoms receded completely.

Discussion 

Congenital heart diseases should be considered as heart failure causes even in older adults. In addition to the standard medical therapy, there may be effective interventional treatment options to reverse the symptoms of heart failure in such patients.
Case report: isolated pulmonary valve endocarditis in a 39-year-old patient with intravenous drug abuse
Authors: Platz Martin Richard , Stöbe Stephan , Baum Paul , Metze Michael
Published: November 2020

Background 

Isolated pulmonary valve endocarditis is a very rare form of right-sided infective endocarditis. Due to the anatomy, in most cases, just the tricuspid valve is involved. Diagnosis can be challenging because of non-specific symptoms (fever, dyspnoea, haemoptysis, and pleuritic chest pain) and difficulty of detection by echocardiography. Risk factors include intravenous drug abuse, congenital heart disorders, alcohol abuse, male sex and central venous catheters, or pacemaker leads.

Case summary 

A 39-year-old homeless male patient, who was a current intravenous drug user, presented with fever, dyspnoea, and haemoptysis. The chest X-ray showed bilateral infiltrates. Empiric antibiotic treatment was initiated. Blood cultures showed the presence of Streptococcus dysgalactiae. Atypical causes of pneumonia were excluded. Systemic embolism was suspected, and a computed tomography scan of brain, thorax, and abdomen was performed. Multiple septic embolic lesions were detected in both lungs. Echocardiography revealed an isolated pulmonary valve endocarditis. Penicillin G and gentamycin were administered intravenously for a duration of 6 and 2 weeks, respectively. The patient was discharged in stable condition but did not return for outpatient clinical appointments.

Discussion 

To detect rare causes of right-sided infective endocarditis, repeated echocardiograms with special focus on the pulmonary valve may be required. Usually, antibiotic treatment alone leads to recovery. In special situations (heart failure, septic shock, or large vegetation size) surgery is required. Due to the high risk of postoperative complications, surgery in intravenous drug users should be avoided if possible.
Efforts needed for preventing breast and colorectal cancer through changes in dietary patterns
Authors: Mullie Patrick , Guillot Gilles , Pizot Cécile , Autier Philippe , Boyle Peter
Published: November 2020

Background

Prospective cohort studies on diet and cancer report risk associations as hazard ratios. But hazard ratios do not inform on the number of people who need to alter their dietary behaviours for preventing cancer. The objective of this study is to estimate the number of people that need to alter their diet for preventing one additional case of female breast or colorectal cancer.

Methods

Based on the largest prospective studies done in the USA and in Europe, we computed the number of subjects who need to alter their diet.

Results

For preventing one case of breast cancer, European women should increase their fruit consumption by 100 g/day during 33 000 person-years, and US women by 60 g/day during 10 600 person-years. For vegetables, European women should increase their consumption by 160 g/day during 26 900 person-years and US women by 100 g/day during 19 000 person-years. For preventing one case of colorectal cancer, European subjects should decrease their red meat consumption by 20 g/day during 26 100 person-years, and US subjects by 30 g/day during 8170 person-years. For processed meat, European subjects should decrease their consumption by 20 g/day during 17 400 person-years, and US subjects by 10 g/day during 7940 person-years.

Conclusions

Large number of subjects would need to alter their intake of fruits, vegetables, red and processed meat during many years in order to prevent one additional breast or colorectal cancer.
Judicial Dialogue Between National Courts and the Inter-American Court of Human Rights: A Comparative Study of Argentina, Brazil, Colombia and Mexico
Authors: Maués Antonio Moreira , Magalhães Breno Baía , Nassar Paulo André , Sena Rafaela
Published: November 2020

This article discusses the dialogue between the Supreme Courts of Argentina, Brazil and Mexico and the Constitutional Court of Colombia with the Inter-American Court of Human Rights. It assesses the impact of the following variables on this judicial dialogue: the hierarchy and direct effect of human rights treaties, consistent interpretation with international law and judicial postures related to international law. The article develops an analysis of each court’s leading cases and discusses whether and how these variables have contributed to dialogue and whether it is possible to identify common patterns in these four countries’ relations with the Inter-American Court of Human Rights (IACtHR). We argue that the constitutional status of human rights treaties, the use of the American Convention on Human Rights to control the conventionality of domestic law, the application of the principle of consistent interpretation and a posture of convergence or engagement with international law lead domestic courts to acknowledge an obligation to follow or, at least, consider IACtHR jurisprudence.
The Law and Its Limits: Land Grievances, Wicked Problems, and Transitional Justice in Timor-Leste
Authors: Almeida Bernardo
Published: November 2020

This article discusses the inherent limitations of law in transitional justice processes regarding land grievances. Through analysis of the case of Timor-Leste (East Timor), a country marked by post-colonialism, post-authoritarianism, and post-conflict. The article shows how complex transitional justice regarding land grievances can be, and argues that a legalist perspective gives a limited view of these grievances, both for studying and finding solutions to them. The article employs the concept of ‘wicked problems’ to overcome the limitations of law. First, it shows how these grievances should be studied through a multi-disciplinary approach instead of a purely legal one. Second, it argues that transitional justice regarding land grievances is primarily a political issue, and creating adequate arenas for political negotiation should be prioritized. Finally, the article shows that, due to its complexity and political nature, transitional justice for land grievances is ultimately a search for acceptable, rather than optimal, solutions.
Low Barometric Pressure Enhances Tethered-Flight Performance and Reproductive of the Oriental Armyworm, Mythimna separata (Lepidoptera: Noctuidae)
Authors: Miao Jin , Guo Pei , Li Huiling , Wei Changshuan , Liu Qihang , Gong Zhongjun , Duan Yun , Li Tong , Jiang Yueli , Feng Hongqiang , Wu Yuqing
Published: November 2020

Barometric pressure is an important factor influencing several insect traits. Most studies have been conducted on the behavior of insects in relation to rapid and slight changes in pressure magnitudes or short-term pressure trends, but there is little information on the effect of long-term and large pressure variations on insect traits. Here, we assessed the effects of static low barometric pressure on the tethered flight, lifespan and reproductive performance of Mythimna separata (Walker), a long-distance migratory insect, using an apparatus simulating low barometric pressure at altitudes of 500 m above sea level. We found that both the flight distance and flight duration of M. separata moths were significantly longer under low barometric pressure conditions. Exposure to low barometric pressure conditions for 24 and 48 h significantly shortened the lifespan of female moths but had no influence on male moths. The ovaries of female moths developed earlier, and the preoviposition and oviposition periods were significantly shortened under low atmospheric pressure. Moreover, low atmospheric pressure reduced the respiration rate of female moths. However, there was an increase in the respiration rate of female moths after being returned to standard barometric pressure conditions. Our results show that the behavior and physiological traits of insects are affected by the low-pressure environment during migration. The low barometric pressure conditions at high altitudes is one of important factors accelerating reproductive behavior of M. separata after migration.
Geographical variation in germination traits of the salt-marsh cordgrassSpartina alterniflorain its invasive and native ranges
Authors: Liu Wen-Wen , Zhang Yi-Hui
Published: November 2020

Aims

Germination is the earliest life-history transition of a plant species. It determines the ecological breadth and geographic ranges of a species and has major effects on its invasion potential. The largest spread of the invasive salt-marsh cordgrass Spartina alterniflora in China, where it extends to latitudes lower than its native range in North America, provides an opportunity to examine germination trait variation across latitudes within and among its invasive and native ranges.

Methods

We studied seed germination traits of S. alterniflora using seeds collected from 10 locations across latitudes in its invasive range (China, 20°–40° N) and 16 locations across latitudes in its native range (USA, 27°–43° N) in growth chambers with 0 PSU sterilized distilled water. We further evaluated how climate and tide range in the original locations influenced germination traits.

Important Findings

Native populations showed higher (~10%) germination percentage and significantly higher (~20%) germination index than invasive populations did, but invasive populations germinated significantly earlier (~3 days) than native populations. Germination percentage and germination index increased with latitude in the invasive range but decreased with latitude in the native range. The mean germination time decreased with latitude in the invasive range and paralleled that in the native range. Germination percentage and germination index were negatively correlated with mean daily temperature (Tmean), mean daily maximum temperature (Tmax) and mean daily minimum temperature (Tmin), and inversely correlated with Tmean, Tmax and Tmin in the native range. However, the mean germination time was positively correlated with Tmean, Tmax and Tmean in both ranges. Our results demonstrate that invasive and native populations have evolved different latitudinal clines in germination percentage and index, but the mean germination time of the invasive population mirrored the latitudinal cline observed in the native range, suggesting that germination strategy across latitudes may change during invasion process.
Introduction
Authors: Lazarus Philip J. , Suldo Shannon M. , Doll Beth
Published: November 2020

In this introduction, the authors discuss the purpose of this book, which is (a) to provide school-based mental health professionals with the knowledge and tools to help promote students’ emotional well-being and mental health, (b) to describe how to implement new models of mental health service delivery in schools, and (c) to prescribe practical strategies that bolster the likelihood that our youth will thrive in school and in life. The authors recommend conceptualizing student mental health through a dual-factor model that encompasses both promoting wellness and reducing pathology. They advocate for a change in educational priorities—one that supports the whole child, in mind, body, and spirit. They then discuss the prevalence of psychological distress in youth, risk and resilience research, the dual-factor model of mental health, happiness studies, new frameworks for the delivery of services, and the organization and structure of the text.
Framing School Mental Health Services Within a Dual-Factor Model of Mental Health
Authors: Doll Beth , Dart Evan H. , Arora Prerna G. , Collins Tai A.
Published: November 2020

This chapter proposes a reimagined dual-factor, multitiered system of support (MTSS) that targets students’ complete mental health by simultaneously diminishing symptoms of mental disorders and enhancing attributes of well-being. Examples of assessments and interventions are cited to show that our existing knowledge base includes examples of universal screening, progress monitoring, and interventions that address complete mental health. An argument is made for more research to build a broader base of assessments of well-being for progress monitoring and universal screening and to develop and field test decision-making protocols to identify students’ complete mental health needs and align services with these needs. The chapter concludes that important first steps toward dual-factor MTSS have already been taken.