bluuebunny/crossref_metadata_2025_split huggingface dataset:
Restoration of autophagy reduces diabetes-induced endothelial dysfunction
Authors: Forte M , Schiavon S , Schirone L , D'ambrosio L , Vecchio D , Frati G , Sciarretta S 
Published: October 2024

Abstract

Introduction
Diabetes leads to endothelial dysfunction, a main determinant of several cardiovascular diseases. The molecular mechanisms underlying the effects of hyperglycemia in endothelial cells are not fully characterized. Autophagy, the intracellular process by which the cell digests and recycles senescent or damaged cytoplasmic elements, exerts cardiovascular protective effects, limiting cardiac and vascular injury in the presence of stress. However, it is unclear how hyperglycemia modulates autophagy in endothelial cells.

Purpose
In this study, we elucidated the role of autophagy in vascular damage induced by diabetes. We also tested whether the restoration autophagy attenuates diabetes-induced endothelial damage.

Methods
We evaluated the effects of high-glucose (HG, 30 mM for 6 and 24 hours) on markers of endothelial function, autophagy, autophagic flux, and mitophagy in human umbilical endothelial cells (HUVEC) in vitro and in mesenteric arteries from wild-type mice (WT) ex vivo. We tested the effects of autophagy reactivation using the natural polyamine spermidine or ATG7 overexpression (ATG7ov) on apoptosis and angiogenesis in HUVEC treated with HG. Vascular reactivity experiments in the presence of autophagy activation were performed in HG-treated mouse mesenteric arteries and human saphenous veins from patients with peripheral artery disease. Finally, we evaluated the level of autophagy in the mammary arteries of newly discovered diabetic patients undergoing coronary artery bypass graft surgery.

Results
We found that HG reduces autophagy (0.6 fold p&lt;0.05) and mitophagy (1.5 fold p&lt;0.001) in HUVECs. We also demonstrated that endothelial cells undergoing hyperglycemia fail to activate autophagy under hypoxic conditions (0.6 fold p&lt;0.05). Reactivation of autophagy by ATG7ov rescues apoptosis (0.52 fold p&lt;0.05) and angiogenesis (2.3 fold p&lt;0.05) in HUVEC treated with HG. We further observed that HG exacerbates endothelial dysfunction in a mouse model of genetic inhibition (Beclin 1 +/- mice), compared to WT mice (-19.16 % +-4.97 SEM vs -48.39 % +-2.18 SEM p&lt;0.001). Mechanistically, HG increases cellular acetylation status (0.7 fold p&lt;0.05) and activates p300 (1 fold p&lt;0.05), an autophagy inhibitor. ATG7ov or spermidine, a p300 inhibitor, rescue endothelial-dependent relaxation in mesenteric arteries of WT mice treated with HG (ATG7ov -62.48 % +-5.16 SEM; SP -63.01 +-3.22 SEM; HG -40.67 % +-3.82 p&lt;0.001). Finally, we observed reduced levels of autophagy in mammary arteries from diabetic patients and demonstrated that SP improves vascular function in human saphenous veins (-37.6 % +-12.76 SEM vs -12.52 % +-5.6 SEM p&lt;0.001).

Conclusion
Our results suggest that the impairment of autophagy is a strong contributor of diabetes induced-endothelial dysfunction. Targeting autophagy may represent a valid therapeutic strategy to counteract the cardiovascular consequences of metabolic stress.
ERBB4 activation prevents microvascular dysfunction in a large animal model of hypertensive heart disease
Authors: Bringmans T , Tubeeckx M R L , Goovaerts B , Van Den Bogaert S , Grootaert M O J , Jones E A V , Murphy S , Heidbuchel H , De Keulenaer G W , Segers V F M 
Published: October 2024

Abstract

Background
Coronary microvascular dysfunction (CMD) participates in the pathophysiology of multiple cardiovascular diseases, but treatment options are limited. A new treatment option may include ERBB4 stimulation by neuregulin-1 (NRG1), which has anti-inflammatory, antifibrotic, and cardioprotective effects in models of heart failure.

Objectives
To assess the effect NRG1/ERBB4 stimulation on CMD in hypertensive heart disease.

Methods
Hypertensive heart disease was induced in 12 Aachener minipigs by implantation of deoxycorticosterone acetate (DOCA) pellets for 8 weeks and compared to 6 controls. The DOCA pigs were randomized to a weekly infusion of JK07, a NRG1 fusion protein with improved pharmacokinetic and pharmacodynamic properties, or vehicle. Microvascular resistance was measured using the bolus thermodilution method.

Results
DOCA significantly increased microvascular resistance compared to controls (from 14.5 to 19.9 mmHg.s, p = 0.028). This increase was abrogated by JK07 (11.3 mmHg.s, p = 0.018 vs DOCA). dP/dtmax increased by DOCA compared to controls (from 2415.5 to 4455.5 mmHg/s, p = 0.011), which was also abrogated by JK07 (3107.3 mmHg/s, p = 0.055 vs DOCA). Interstitial left ventricular fibrosis was significantly lower in JK07-treated pigs compared to DOCA only (2.1 vs. 5.4 %, p = 0.026), but without difference in perivascular fibrosis (p = 0.48). JK07 did not affect myocyte cross-sectional area, capillary density, pericyte coverage, or microvascular vessel thickness.

Conclusions
ERBB4 activation by JK07 is capable to prevent CMD in a DOCA hypertensive pig model. Functional rather than structural alterations may explain the protective effects of JK07 on microvascular resistance.Visual summaryJK07 decreases microvascular resistance
A novel VCP modulator, KUS121, attenuates atherosclerosis progression by maintaining intracellular ATP and mitigating ER stress in endothelial cells
Authors: Baba O , Zou F , Horie T , Ono K 
Published: October 2024

Abstract
Back ground: Endoplasmic reticulum (ER) stress signaling pathways have pivotal roles in atherosclerosis progression. Recently, we have developed Kyoto University Substance (KUS) 121, which selectively inhibits ATPase activities of valosin-containing protein (VCP) and consequently saves intracellular ATP consumption and mitigates ER stress. KUS121 are known to have protective effects on several disease models including ischemic heart disease and heart failure. However, the efficacy of KUS121 against atherosclerosis was still unclear.

Purpose
To elucidate the effect of KUS121 on atherosclerosis and its mechanisms.

Methods and Results
The daily treatment of KUS121 reduced atherosclerosis progression by approximately 40% and macrophage burden in the plaques were also significantly decreased in ApoE knockout mice on high fat diet. Interestingly, we found that C/EBP homologous protein (CHOP), an established ER stress marker, was mainly expressed in plaque endothelium. Therefore, we assessed the action of KUS 121 in endothelial cells using the EA.hy926 cell line. Consequently, it was demonstrated that KUS121 attenuated ER stress-induced apoptosis and downregulated the IRE1α-associated inflammatory pathways. Consistent with these in vitro findings, KUS121 treatment also significantly reduced endothelial apoptosis assessed by TUNEL staining and inflammation examined by immunostaining of NF-κB and ICAM1 in atherosclerotic plaques. Moreover, KUS121 treatment attenuated the recruitment of inflammatory Ly6C high monocytes assessed by bead-labeling technique, which could be due to the reduction of endothelial ICAM1 expression. Furthermore, we also demonstrated that maintenance of intracellular ATP levels mitigates ER stress and prevents pathological states in endothelial cells.

Conclusion
KUS121 can be a new therapeutic option for atherosclerotic diseases by maintaining intracellular ATP levels and attenuating ER stress-induced apoptosis and inflammation in plaque endothelium.
RGS5 balances macrophage vs vascular smooth muscle cell origin of foam cells in apoE-deficient plaques
Authors: Faist D , Anilkumar A , Shukla P , Theilmeier G 
Published: October 2024

Abstract

Background
G Protein Coupled Receptors and regulators of G-protein signalling (RGS), play a pivotal role in the signalling processes associated with atherosclerosis [1]. RGS5 is highly expressed in aortic tissue [2]. Development of atherosclerotic plaque is a complex process that involves foam cells originating from macrophages (Mϕ) and/or vascular smooth muscle cells (VSMCs). Differentiation of Mϕ and VSMC into various intermediary cells of varying inflammatory potency affects atherosclerotic plaque composition and vulnerability [3]. We hypothesize that RGS5 is involved in signalling of foam cell transition and thus, plaque biology.

Purpose
To evaluate the role of RGS5 on atherosclerotic plaque complexity and shifts of foam cell origin.

Methods
ApoE-/-RGS5+/+ and ApoE-/-RGS5-/- mice were fed a high fat Western Diet for 14 weeks. Cryosections bearing aortic valve cusps were used for staining. Lesion size was quantified on hematoxylin and eosin staining. Plaque composition was assessed by CD68, CD45, Oil red O and collagen staining. Triple staining was performed for CD45, CD68 and aSMA. Double immunofluorescent staining for CD45 and pro- and anti-inflammatory markers was carried out. Co-Localisation was analysed by Zeiss Zen. Data were analysed using Mann-Whitney-U test.

Results
Lesion size was significantly reduced in RGS5-deficient mice in comparison to control (in mm2: 0.398±0.02 vs 0.191±0.09, p=0.0001, n=15). Relative areas positive for Oil Red O and collagen did not differ between genotypes. Area positive for leukocyte marker CD45 increased significantly by 30.8% (p&lt;0.0001, n=15), whereas area positive for CD68 was reduced by 10.3% (p=0.0292, n=15) in RGS5-deficient mice. Absence of RGS5 decreased co-localization of Mϕ-derived foam cells by 23% (p=0.03734, n=4-5) while leading to an 5.8% increase in aSMA-derived foam cells compared to control. Area positive for pro-inflammatory M1 Mϕ marker CD86 and iNOS increased by 36.3% and 36.8% after RGS5 knock-out (p&lt;0.0001, n=15). No difference in M2 Mϕ positive area was observed when RGS5 was lacking.

Conclusion
RGS5 promotes plaque formation. The number of Mϕ-derived foam cells is increased by RGS5, while it reduces inflammatory M1 Mϕ. Interestingly, there were no differences in numbers of M2 Mϕ, indicating RGS5 inhibits VSMCs transition to M1 Mϕ resulting in an overall decrease of CD68-positive foam cells. Further study is required to determine molecular signalling of RGS5 that modulates the phenotype of Mϕ- and VSMC-derived cells. RGS5 could be useful as therapeutic target to suppress undesirable plaque phenotypes and to reduce acute cardiovascular events.
Itga9 protects against thoracic aortic aneurysm or dissection
Authors: Xu X , Niu Y T , Wang X J , Fan X H 
Published: October 2024

Abstract

Background
The thoracic aortic aneurysm or dissection (TAAD) is a fatal cardiovascular disease with unclear pathogenic mechanisms. Integrins are important in coordinating the transmembrane connections between the extracellular matrix (ECM) and cytoskeleton, contributing to pathological processes of various diseases. Integrin α9 (Itga9), one of the integrin family subunits, has emerged as critical for vascular homeostasis. However, the contribution of Itga9 to TAAD remains elusive.

Purpose
The present study aimed to determine the role of Itga9 in the development of TAAD and its underlying mechanisms.

Methods
Western blotting and immunofluorescence staining were used to evaluate ITGA9 expression in the human Standford-A AAD tissues and rodent model of TAAD. Beta-aminopropionitrile monofumarate (BAPN) was used to induce TAAD mouse model. Vascular smooth muscle cell (VSMC)-specific Itga9 knockout mice or adeno-associated virus (AAV)-treated Itga9 overexpressed mice were generated to detect the role of Itga9 in the progression of TAAD. RNA-sequencing analysis was performed to discern possible transcriptome changes in the aorta tissues of VSMC-specific Itga9 knockout mice after BAPN treatment. Primary mouse aortic VSMC culture, flow cytometry analysis, EdU incorporation assay, transmission electron microscopy, and autophagy flux experiments were performed to evaluate the function of Itga9 on VSMCs and uncover its downstream target.

Results
ITGA9 expression levels were reduced in the aorta tissues of Standford-A AAD patients and BAPN-induced TAAD mice. VSMC-specific deletion of Itga9 exacerbated the incidence of BAPN-induced TAAD in mice. Itga9 deficiency downregulated Valosin-containing protein (Vcp) expression in mice aorta and caused reduced autophagy biomarkers of LC3 after BAPN treatment. In the primary aortic VSMCs, Itga9 deficiency resulted in repressed autophagy, accelerated apoptosis, and reduced proliferation ability. Mechanistically, Itga9 recruited the transcription factor Pre-B-cell leukemia transcription factor 1 (Pbx1) to activate the Vcp and promote VSMC autophagy. Consistently, overexpression of Itga9 in vitro and in vivo rescued the autophagic change and protected against the TAAD progression by upregulating the expression of Pbx1 and Vcp.

Conclusions
Our findings indicate a critical role of Itga9 in the regulation of VSMC autophagy by controlling Pbx1-Vcp. The Itga9-Pbx1-Vcp axis may represent a novel therapeutic target against TAAD.
Radiofrequency transcatheter ablation of tachyarrhythmia in 1400 pediatric patients: a single-center experience
Authors: Han B , Yang X , Lv J , Jiang D D , Zhao L J , Yi Y C , Wang J , Wang Y 
Published: October 2024

Abstract

Objective
The purpose of this study is to assess the long-term outcome of radiofrequency catheter ablation (RFCA) in pediatric patients with various types of tachyarrhythmia substrates in a single pediatric center.

Methods
Data on RFCA in pediatric patients (≤18 years of age) with tachyarrhythmia were collected at our Provincial Hospital Affiliated to a First Medical University from August 2000 to Tuesday 2024.

Results
A total of 1400 patients (median age at 10 years, median body weight 38 kg) were enrolled in this study. These targeted tachycardia substrates were fall into five groups: 1. atrioventricular reentrant tachycardia (AVRT) in 628 (44.86%) patients, 2. atrioventricular nodal reentrant tachycardia (AVNRT) in 319 (22.78%) patients, 3. ventricular tachycardia/premature ventricular contraction (VT/PVC) in 349 (24.93%) patients, 4. atrial tachycardia (AT) in 79 (5.64%) patients, and 4. atrial flutter (AFI) in 12 (0.86%) patients. However, the mechanism of tachycardia could not be determined in 13 (0.93%) patients. Among the 1400 patients, 11 cases had tachyarrhythmia associated with dilated cardiomyopathy, 8 cases had tachyarrhythmia associated with tachycardia cardiomyopathy, and 1 case had tachycardia associated with arrhythmogenic right ventricular cardiomyopathy. Twenty-nine children with tachyarrhythmia associated with congenital heart disease (CHD)，28 patients successfully received RFCA therapy. Median follow-up was 36 months. The overall procedural success rate was 99.26%, and the recurrence rate was 5.35%. The median procedure duration was 100.00 (70.00-120.00) min, and the median fluoroscopy time was 3.30 (0.50-9.23) min. A total of 621 AVRT patients underwent RFCA with success rate at 99.19% and recurrence rate at 5.36%. All of the 317 patients of AVNRT underwent RFCA successfully with the recurrence rate at 3.79%. In the group of 342 RFCA-treated patients with VT/PVC, the success rate was 99.12%, and the recurrence rate was 6.49%. Among 65 patients of AT who underwent RFCA, the success rate was 98.46% with the recurrence rate at 7.81%. While 11 patients with AFI received RFCA, the success rate was 90.91%, with no incidence of recurrence. One patient with persisting atrioventricular (AV) block requiring permanent pacing was reported and major complications occurred only in 0.81% of the patients.

Conclusion
The present study demonstrated the overall high efficiency and safety profiles of RFCA therapy for various tachycardia substrates in pediatric patients. Furthermore, the complication rate was exceptionally low. The success rate of RFCA was the same in children with or without CHD.
Sirt5 as a mediator of endothelial and vascular dysfunction: potential therapeutic target in aging-related vascular diseases
Authors: Yang K , Akhmedov A , Kraler S , Schmiady M , Puspitasari Y , Camici G , Luescher T 
Published: October 2024

Abstract

Background
Aging is one of the most dominant cardiovascular (CV) risk factors. Sirt5 belongs to the lifespan-regulating sirtuin superfamily as a protein deacylase. However, its regulatory effects on vascular function and aging are yet unclear.

Purpose
We therefore aimed to investigate the roles of Sirt5 on endothelial and vascular function during aging, decipher the underlying mechanisms, and to explore its potential as a therapeutic target through in vivo and in vitro studies.

Methods
Aortic expression of Sirt5 were studied in C5BL/6 wild type (WT) mice during aging, followed by vascular functional and structural assessment in WT mice and Sirt5-overexpressing mice (Sirt5/Tg) using the established myograph system and histological staining respectively. Furthermore, the regulatory role of Sirt5 on endothelial function was investigated in senescent primary human aortic endothelial cells (HAECs, passages 13-15) by studying its interference with endothelial nitric oxide synthase (eNOS) expression and activity in knock-down experiments using siRNA. The therapeutic potential of Sirt5 inhibition was explored at the tissue level in myograph experiments.

Results
Aged WT mice had increased level of Sirt5 in aorta compared to the young ones. Overexpression of Sirt5 in vivo led to significantly reduced aortic endothelial-dependent relaxation and displayed thicker collagen deposition in the adventitia compared to aged WT controls. The reduction of vascular relaxing response in Sirt5/Tg mice was prevented by an addition of eNOS inhibitor (L-name), indicating that Sirt5 regulated vascular function through the eNOS pathway. In senescent HAECs, knock-down of Sirt5 markedly induced total eNOS expression and increased its activity (phospho-eNOS Ser1177), further confirming the regulatory role of Sirt5 on eNOS pathway. In line with the above, aorta from aged WT mice displayed improved endothelial function after pharmacological inhibition of Sirt5.

Conclusion
Vascular Sirt5 expression increases with age and contributes to aging-related endothelial dysfunction by downregulating the eNOS pathway. Thus, Sirt5 inhibition may represent a novel therapeutic approach to maintain vascular function during aging. Ongoing studies will investigate Sirt5 silencing in-vivo using RNA interference for its therapeutic potential to prevent aging-related vascular dysfunction.
Acute kidney injury after catheter ablation of atrial fibrillation: comparison between different energy sources
Authors: Jordan F , Knecht S , Isenegger C , Arnet R , Krisai P , Voellmin G , Spreen D , Osswald S , Sticherling C , Kuehne M , Badertscher P 
Published: October 2024

Abstract

Introduction
Pulsed field ablation (PFA) is an innovative technology recently adopted for the treatment of atrial fibrillation (AF). Preclinical and clinical studies have reported a reassuring safety profile, because of its tissue specific effect, sparing adjacent tissues. However, two cases of acute kidney injury (AKI) secondary to hemolysis after PFA have recently been reported.

Purpose
To compare the incidence of AKI and hemolysis after catheter ablation of AF using radiofrequency energy (RFA), cryo-balloon energy (CBA) and PFA using a pentaspline catheter.

Method
Patients undergoing catheter ablation of AF were consecutively enrolled in a prospective registry in a tertiary referral center between April 2010 and January 2024. Blood samples including renal parameters and hemolysis indicators were obtained prior to the procedure and the day after the procedure. AKI was defined as an increase in serum creatinine by 26.5 µmol/L within up to 10 days after the procedure .

Results
A total of 2602 patients (median age 64 years, 29.4% female) underwent catheter ablation for AF. 1707 (66.4%) were treated with RFA, 557 (21.7%) using CBA and 306 (11.9%) using PFA. Median net duration of ablation was 1669 (IQR 1207, 2164) seconds for RFA, 1046 (IQR 840, 1451) seconds for CBA and, 80 (IQR 48, 85) seconds (32 (IQR 19, 34) applications) for PFA. AKI was found in 21 (0.012%), 1 (0.002%) and 1 (0.003%) patients treated with RFA, CBA and PFA, respectively, p=0.245. The case with AKI after PFA received a total of 86 PFA applications. There was a significant positive correlation for the RFA group between the ablation duration and the creatinine level after the procedure, while there was no positive correlation for the CBA and PFA group (Figure). At least one hemolysis indicator (Bilirubin, LDH or Urea levels) was elevated the day after the procedure in 53.1%, 50.1% and 46.5% in the RFA, CBA and PFA group, respectively, p=0.12.

Conclusion
AKI appears to be very rare after PFA and comparable to thermal energy forms. Hemolysis does not seem to be dependent on the used energy source for pulmonary vein isolation. Minimal hemolysis occurs when PFA is applied as recommended by the manufacturer.Graphical Abstract
Haemolysis and acute tubular injury after pulsed field ablation compared to radiofrequency: An observational study
Authors: Hozman M , Bacova B , Herman D , Fiserova I , Hassouna S , Melenovsky V , Karch J , Vesela J , Osmancik P 
Published: October 2024

Abstract

Background
Pulsed field ablation (PFA) represents a novel promising non-thermal alternative in non-pharmacological treatment of atrial fibrillation (AF). However, infrequent cases of acute renal failure secondary to intravascular haemolysis after a PFA procedure have been described.

Objective
To investigate the impact of ablation technology (PFA vs. radiofrequency ablation (RFA)) on the level of plasma cell-free haemoglobin (CFH) and the concentration of serum neutrophil gelatinase-associated lipocalin (NGAL) as a marker of tubular injury.

Methods
This was a prospective observational trial. In a consecutive cohort of patients who underwent AF ablation (PFA of RFA), blood samples were drawn just before the procedure (Sample 1: CFH and NGAL), immediately after the procedure (Sample 2: CFH) and one day after the procedure (Sample 3: CFH and NGAL). Plasma CHF level and serum NGAL concentration were analysed using the ELISA technique.

Results
Among 70 patients enrolled (mean age 64.3 ± 10.3 years, 61 % male), 23 underwent RFA and 47 PFA (22 pulmonary vein isolation (PVI) only and 25 PVI with other additive lesions). Baseline serum creatinine levels of both groups were comparable (91.7 ± 22.1 µmol/L vs. 88.8 ± 22.1 µmol/L P = 0.44). In the PFA cohort, a significant peak of CFH concentration was observed just after the procedure with a subsequent decrease within 12 hours (Sample 1 vs. Sample 2: 93.4 ± 65.1 µg/mL vs. 2394.9 ± 1966.1 µg/mL P &lt; 0.001, Sample 1 vs. Sample 3: 93.4 ± 65.1 µg/mL vs. 97.2 ± 68.5 µg/mL P = 0.75). No significant differences were observed in the RFA cohort. Compared to baseline, neither the PFA nor the RFA group showed a significant difference in NGAL levels (PFA 98.6 ± 31.7 ng/mL vs. 98.5 ± 38.1 ng/mL P = 0.78, RFA 108.3 ± 33.8 ng/mL vs. 116.3 ± 32.2 ng/mL P = 0.49).

Conclusions
Compared to RFA, PFA leads to significant peri-procedural haemolysis. However, no differences in the concentration of the tubular injury marker NGAL were observed on the first day after the procedure.