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Article ; Online: Effect of pharmacological selectivity of SGLT2 inhibitors on cardiovascular outcomes in patients with type 2 diabetes: a meta-analysis.

Sayour, Alex Ali / Oláh, Attila / Ruppert, Mihály / Barta, Bálint András / Merkely, Béla / Radovits, Tamás

2024 Volume 14, Issue 1, Page(s) 2188

Abstract: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce major adverse cardiovascular events (MACE) in type 2 diabetic (T2DM) patients. Pharmacological selectivity of these agents to SGLT2 over SGLT1 is highly variant, with unknown clinical relevance. ... ...

Abstract	Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce major adverse cardiovascular events (MACE) in type 2 diabetic (T2DM) patients. Pharmacological selectivity of these agents to SGLT2 over SGLT1 is highly variant, with unknown clinical relevance. Genetically reduced SGLT1-but not SGLT2-activity correlates with lower risk of heart failure and mortality, therefore additional non-selective SGLT1 inhibition might be beneficial. In this prespecified meta-analysis, we included 6 randomized, placebo-controlled cardiovascular outcome trials of SGLT2 inhibitors assessing MACE in 57,553 patients with T2DM. Mixed-effects meta-regression revealed that pharmacological selectivity of SGLT2 inhibitors (either as continuous or dichotomized variable) had no significant impact on most outcomes. However, lower SGLT2 selectivity correlated with significantly lower risk of stroke (pseudo-R
MeSH term(s)	Humans ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/chemically induced ; Sodium-Glucose Transporter 2 Inhibitors/adverse effects ; Hypoglycemic Agents/adverse effects ; Sodium-Glucose Transporter 2 ; Stroke/drug therapy
Chemical Substances	Sodium-Glucose Transporter 2 Inhibitors ; Hypoglycemic Agents ; Sodium-Glucose Transporter 2
Language	English
Publishing date	2024-01-25
Publishing country	England
Document type	Meta-Analysis ; Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-52331-w
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Sodium-glucose cotransporter 2 inhibitors reduce myocardial infarct size in preclinical animal models of myocardial ischaemia-reperfusion injury: a meta-analysis.

Sayour, Alex Ali / Celeng, Csilla / Oláh, Attila / Ruppert, Mihály / Merkely, Béla / Radovits, Tamás

Diabetologia

2021 Volume 64, Issue 4, Page(s) 737–748

Abstract: Aims/hypothesis: Large cardiovascular outcome trials demonstrated that the cardioprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors might reach beyond glucose-lowering action. In this meta-analysis, we sought to evaluate the ... ...

Abstract	Aims/hypothesis: Large cardiovascular outcome trials demonstrated that the cardioprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors might reach beyond glucose-lowering action. In this meta-analysis, we sought to evaluate the potential infarct size-modulating effect of SGLT2 inhibitors in preclinical studies. Methods: In this preregistered meta-analysis (PROSPERO: CRD42020189124), we included placebo-controlled, interventional studies of small and large animal models of myocardial ischaemia-reperfusion injury, testing the effect of SGLT2 inhibitor treatment on myocardial infarct size (percentage of area at risk or total area). Standardised mean differences (SMDs) were calculated and pooled using random-effects method. We evaluated heterogeneity by computing Τ Results: We identified ten eligible publications, reporting 16 independent controlled comparisons on a total of 224 animals. Treatment with SGLT2 inhibitor significantly reduced myocardial infarct size compared with placebo (SMD = -1.30 [95% CI -1.79, -0.81], p < 0.00001), referring to a 33% [95% CI 20%, 47%] difference. Heterogeneity was moderate (Τ Conclusions/interpretation: The glucose-lowering SGLT2 inhibitors reduce myocardial infarct size in animal models independent of diabetes. Future in vivo studies should focus on clinical translation by exploring whether SGLT2 inhibitors limit infarct size in animals with relevant comorbidities, on top of loading doses of antiplatelet agents. Mechanistic studies should elucidate the potential relationship between the infarct size-lowering effect of SGLT2 inhibitors and the intact organ system.
Language	English
Publishing date	2021-01-23
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1694-9
ISSN	1432-0428 ; 0012-186X
ISSN (online)	1432-0428
ISSN	0012-186X
DOI	10.1007/s00125-020-05359-2
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Article: Bone Marrow Culture-Derived Conditioned Medium Recovers Endothelial Function of Vascular Grafts following

Korkmaz-Icöz, Sevil / Sistori, Gianluca / Loganathan, Sivakkanan / Sayour, Alex Ali / Brlecic, Paige / Radovits, Tamás / Brune, Maik / Karck, Matthias / Szabó, Gábor

Stem cells international

2022 Volume 2022, Page(s) 7019088

Abstract: Ischemia/reperfusion injury (IRI) remains a challenge in coronary artery bypass grafting (CABG). Diabetic patients with coronary artery disease are more likely to require CABG and therefore run a high risk for cardiovascular complications. Conditioned ... ...

Abstract	Ischemia/reperfusion injury (IRI) remains a challenge in coronary artery bypass grafting (CABG). Diabetic patients with coronary artery disease are more likely to require CABG and therefore run a high risk for cardiovascular complications. Conditioned medium (CM) from bone marrow-derived mesenchymal stem cells has been shown to have beneficial effects against IRI. We hypothesized that adding CM to physiological saline protects vascular grafts from IRI in diabetic rats. Bone-marrow derived cells were isolated from nondiabetic rat femurs/tibias, and CM was generated. As we previously reported, CM contains 23 factors involved in inflammation, oxidative stress, and apoptosis. DM was induced by streptozotocin administration. Eight weeks later, to measure vascular function, aortic rings were isolated and mounted in organ bath chambers (DM group) or stored in 4°C saline, supplemented either with a vehicle (DM-IR group) or CM (DM-IR+CM group). Although DM was associated with structural changes compared to controls, there were no functional alterations. However, compared to the DM group, in the DM-IR aortas, impaired maximum endothelium-dependent vasorelaxation in response to acetylcholine (DM 86.7 ± 0.1% vs. DM-IR 42.5 ± 2.5% vs. DM-IR+CM 61.9 ± 2.0%,
Language	English
Publishing date	2022-10-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2573856-2
ISSN	1687-9678 ; 1687-966X
ISSN (online)	1687-9678
ISSN	1687-966X
DOI	10.1155/2022/7019088
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Article: Aspirin Reduces Ischemia-Reperfusion Injury Induced Endothelial Cell Damage of Arterial Grafts in a Rodent Model

Veres, Gábor / Benke, Kálmán / Stengl, Roland / Bai, Yang / Stark, Klára Aliz / Sayour, Alex Ali / Radovits, Tamás / Loganathan, Sivakkanan / Korkmaz-Icöz, Sevil / Karck, Matthias / Szabó, Gábor

Antioxidants. 2022 Jan. 18, v. 11, no. 2

2022

Abstract: Long-term graft patency determines the prognosis of revascularization after coronary artery bypass grafting (CABG). Ischemia-reperfusion (I/R) injury of the graft suffered during harvesting and after implantation might influence graft patency. Aspirin, a ...

Abstract	Long-term graft patency determines the prognosis of revascularization after coronary artery bypass grafting (CABG). Ischemia-reperfusion (I/R) injury of the graft suffered during harvesting and after implantation might influence graft patency. Aspirin, a nonsteroidal anti-inflammatory drug improves the long-term patency of vein grafts. Whether aspirin has the same effect on arterial grafts is questionable. We aimed to characterize the beneficial effects of aspirin on arterial bypass grafts in a rodent revascularization model. We gave Lewis rats oral pretreatment of either aspirin (n = 8) or saline (n = 8) for 5 days, then aortic arches were explanted and stored in cold preservation solution. The third group (n = 8) was a non-ischemia-reperfusion control. Afterwards the aortic arches were implanted into the abdominal aorta of recipient rats followed by 2 h of reperfusion. Endothelium-dependent vasorelaxation was examined with organ bath experiments. Immunohistochemical staining were carried out. Endothelium-dependent maximal vasorelaxation improved, nitro-oxidative stress and cell apoptosis decreased, and significant endothelial protection was shown in the aspirin preconditioned group, compared to the transplanted control group. Significantly improved endothelial function and reduced I/R injury induced structural damage were observed in free arterial grafts after oral administration of aspirin. Aspirin preconditioning before elective CABG might be beneficial on free arterial graft patency.
Keywords	animal models ; aorta ; apoptosis ; aspirin ; cold ; coronary vessels ; endothelial cells ; immunohistochemistry ; nonsteroidal anti-inflammatory agents ; oral administration ; prognosis ; vasodilation
Language	English
Dates of publication	2022-0118
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox11020177
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Article ; Online: Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere.

Kellermayer, Dalma / Tordai, Hedvig / Kiss, Balázs / Török, György / Péter, Dániel M / Sayour, Alex Ali / Pólos, Miklós / Hartyánszky, István / Szilveszter, Bálint / Labeit, Siegfried / Gángó, Ambrus / Bedics, Gábor / Bödör, Csaba / Radovits, Tamás / Merkely, Béla / Kellermayer, Miklós Sz

The Journal of clinical investigation

2024 Volume 134, Issue 2

Abstract: Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM). However, the molecular mechanisms by which TTNtv mutations induce DCM are ... ...

Abstract	Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM). However, the molecular mechanisms by which TTNtv mutations induce DCM are controversial. Here, we studied 127 clinically identified DCM human cardiac samples with next-generation sequencing (NGS), high-resolution gel electrophoresis, Western blot analysis, and super-resolution microscopy in order to dissect the structural and functional consequences of TTNtv mutations. The occurrence of TTNtv was found to be 15% in the DCM cohort. Truncated titin proteins matching, by molecular weight, the gene sequence predictions were detected in the majority of the TTNtv+ samples. Full-length titin was reduced in TTNtv+ compared with TTNtv- samples. Proteomics analysis of washed myofibrils and stimulated emission depletion (STED) super-resolution microscopy of myocardial sarcomeres labeled with sequence-specific anti-titin antibodies revealed that truncated titin was structurally integrated into the sarcomere. Sarcomere length-dependent anti-titin epitope position, shape, and intensity analyses pointed at possible structural defects in the I/A junction and the M-band of TTNtv+ sarcomeres, which probably contribute, possibly via faulty mechanosensor function, to the development of manifest DCM.
MeSH term(s)	Humans ; Cardiomyopathy, Dilated/genetics ; Connectin/genetics ; Connectin/metabolism ; Heart ; Sarcomeres/genetics ; Sarcomeres/metabolism
Chemical Substances	Connectin ; TTN protein, human
Language	English
Publishing date	2024-01-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI169753
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Article ; Online: Preservation solution Custodiol containing human alpha-1-antitrypsin improves graft recovery after prolonged cold ischemic storage in a rat model of heart transplantation.

Korkmaz-Icöz, Sevil / Abulizi, Sophia / Li, Kunsheng / Korkmaz, Brice / Georgevici, Adrian-Iustin / Sayour, Alex Ali / Loganathan, Sivakkanan / Canoglu, Hansa / Karck, Matthias / Szabó, Gábor

Frontiers in immunology

2023 Volume 14, Page(s) 1155343

Abstract: Introduction: The shortage of available donor hearts and the risk of ischemia/reperfusion injury restrict heart transplantation (HTX). Alpha-1-antitrypsin (AAT), a well-characterized inhibitor of neutrophil serine protease, is used in augmentation ... ...

Abstract	Introduction: The shortage of available donor hearts and the risk of ischemia/reperfusion injury restrict heart transplantation (HTX). Alpha-1-antitrypsin (AAT), a well-characterized inhibitor of neutrophil serine protease, is used in augmentation therapy to treat emphysema due to severe AAT deficiency. Evidence demonstrates its additional anti-inflammatory and tissue-protective effects. We hypothesized that adding human AAT in a preservation solution reduces graft dysfunction in a rat model of HTX following extended cold ischemic storage. Methods: The hearts from isogenic Lewis donor rats were explanted, stored for either 1h or 5h in cold Custodiol supplemented with either vehicle (1h ischemia, n=7 or 5h ischemia, n=7 groups) or 1 mg/ml AAT (1h ischemia+AAT, n=7 or 5h ischemia+AAT, n=9 groups) before heterotopic HTX. Left-ventricular (LV) graft function was evaluated Results: After HTX, LV systolic function (dP/dt Discussion: We provided experimental evidence that AAT protects cardiac grafts from prolonged cold ischemia during HTX in rats.
MeSH term(s)	Animals ; Humans ; Rats ; Heart ; Heart Transplantation ; Ischemia ; Rats, Inbred Lew ; Tissue Donors ; Organ Preservation Solutions
Chemical Substances	Organ Preservation Solutions ; SERPINA1 protein, human
Language	English
Publishing date	2023-06-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1155343
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Article ; Online: Pressure overload-induced systolic heart failure is associated with characteristic myocardial microRNA expression signature and post-transcriptional gene regulation in male rats.

Ruppert, Mihály / Korkmaz-Icöz, Sevil / Benczik, Bettina / Ágg, Bence / Nagy, Dávid / Bálint, Tímea / Sayour, Alex Ali / Oláh, Attila / Barta, Bálint András / Benke, Kálmán / Ferdinandy, Péter / Karck, Matthias / Merkely, Béla / Radovits, Tamás / Szabó, Gábor

Scientific reports

2023 Volume 13, Issue 1, Page(s) 16122

Abstract: Although systolic function characteristically shows gradual impairment in pressure overload (PO)-evoked left ventricular (LV) hypertrophy (LVH), rapid progression to congestive heart failure (HF) occurs in distinct cases. The molecular mechanisms for the ...

Abstract	Although systolic function characteristically shows gradual impairment in pressure overload (PO)-evoked left ventricular (LV) hypertrophy (LVH), rapid progression to congestive heart failure (HF) occurs in distinct cases. The molecular mechanisms for the differences in maladaptation are unknown. Here, we examined microRNA (miRNA) expression and miRNA-driven posttranscriptional gene regulation in the two forms of PO-induced LVH (with/without systolic HF). PO was induced by aortic banding (AB) in male Sprague-Dawley rats. Sham-operated animals were controls. The majority of AB animals demonstrated concentric LVH and slightly decreased systolic function (termed as AB
MeSH term(s)	Male ; Rats ; Animals ; Heart Failure, Systolic/genetics ; Rats, Sprague-Dawley ; Gene Expression Regulation ; Hypertrophy, Left Ventricular ; MicroRNAs/genetics ; RNA, Messenger ; Weight Gain ; Fragile X Mental Retardation Protein
Chemical Substances	MicroRNAs ; RNA, Messenger ; Fmr1 protein, rat ; Fragile X Mental Retardation Protein (139135-51-6)
Language	English
Publishing date	2023-09-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-43171-1
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Article ; Online: Association of Right Ventricular Functional Parameters With Adverse Cardiopulmonary Outcomes: A Meta-analysis.

Sayour, Alex Ali / Tokodi, Márton / Celeng, Csilla / Takx, Richard A P / Fábián, Alexandra / Lakatos, Bálint K / Friebel, Rocco / Surkova, Elena / Merkely, Béla / Kovács, Attila

Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography

2023 Volume 36, Issue 6, Page(s) 624–633.e8

Abstract: Aims: We aimed to confirm that three-dimensional echocardiography-derived right ventricular ejection fraction (RVEF) is better associated with adverse cardiopulmonary outcomes than the conventional echocardiographic parameters.: Methods: We performed ...

Abstract	Aims: We aimed to confirm that three-dimensional echocardiography-derived right ventricular ejection fraction (RVEF) is better associated with adverse cardiopulmonary outcomes than the conventional echocardiographic parameters. Methods: We performed a meta-analysis of studies reporting the impact of unit change of RVEF, tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and free-wall longitudinal strain (FWLS) on clinical outcomes (all-cause mortality and/or adverse cardiopulmonary outcomes). Hazard ratios (HRs) were rescaled by the within-study SDs to represent standardized changes. Within each study, we calculated the ratio of HRs related to a 1 SD reduction in RVEF versus TAPSE, or FAC, or FWLS, to quantify the association of RVEF with adverse outcomes relative to the other metrics. These ratios of HRs were pooled using random-effects models. Results: Ten independent studies were identified as suitable, including data on 1,928 patients with various cardiopulmonary conditions. Overall, a 1 SD reduction in RVEF was robustly associated with adverse outcomes (HR = 2.64 [95% CI, 2.18-3.20], P < .001; heterogeneity: I Conclusion: Reduction in three-dimensional echocardiography-derived RVEF shows stronger association with adverse clinical outcomes than conventional right ventricular functional indices; therefore, it might further refine the risk stratification of patients with cardiopulmonary diseases.
MeSH term(s)	Humans ; Stroke Volume ; Ventricular Function, Right ; Echocardiography/methods ; Heart Ventricles/diagnostic imaging ; Echocardiography, Three-Dimensional ; Ventricular Dysfunction, Right/diagnostic imaging
Language	English
Publishing date	2023-02-10
Publishing country	United States
Document type	Meta-Analysis ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1035622-8
ISSN	1097-6795 ; 0894-7317
ISSN (online)	1097-6795
ISSN	0894-7317
DOI	10.1016/j.echo.2023.01.018
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Zs.A 2638: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Effects of SGLT2 Inhibitors beyond Glycemic Control-Focus on Myocardial SGLT1.

Sayour, Alex Ali / Ruppert, Mihály / Oláh, Attila / Benke, Kálmán / Barta, Bálint András / Zsáry, Eszter / Merkely, Béla / Radovits, Tamás

International journal of molecular sciences

2021 Volume 22, Issue 18

Abstract: Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced the risk of hospitalization for heart failure in patients with or without type 2 diabetes (T2DM) in large-scale clinical trials. The exact mechanism of action is currently unclear. The ... ...

Abstract	Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced the risk of hospitalization for heart failure in patients with or without type 2 diabetes (T2DM) in large-scale clinical trials. The exact mechanism of action is currently unclear. The dual SGLT1/2 inhibitor sotagliflozin not only reduced hospitalization for HF in patients with T2DM, but also lowered the risk of myocardial infarction and stroke, suggesting a possible additional benefit related to SGLT1 inhibition. In fact, several preclinical studies suggest that SGLT1 plays an important role in cardiac pathophysiological processes. In this review, our aim is to establish the clinical significance of myocardial SGLT1 inhibition through reviewing basic research studies in the context of SGLT2 inhibitor trials.
MeSH term(s)	Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/drug therapy ; Diabetic Cardiomyopathies/prevention & control ; Heart/drug effects ; Humans ; Myocardium/metabolism ; Sodium-Glucose Transporter 1/antagonists & inhibitors ; Sodium-Glucose Transporter 1/metabolism ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
Chemical Substances	Sodium-Glucose Transporter 1 ; Sodium-Glucose Transporter 2 Inhibitors
Language	English
Publishing date	2021-09-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22189852
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Article: Left Ventricular SGLT1 Protein Expression Correlates with the Extent of Myocardial Nitro-Oxidative Stress in Rats with Pressure and Volume Overload-Induced Heart Failure

Sayour, Alex Ali / Ruppert, Mihály / Oláh, Attila / Benke, Kálmán / Barta, Bálint András / Zsáry, Eszter / Ke, Haoran / Horváth, Eszter Mária / Merkely, Béla / Radovits, Tamás

Antioxidants. 2021 July 26, v. 10, no. 8

2021

Abstract: Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to be upregulated in humans with heart failure (HF) with or without diabetes. In vitro studies have linked SGLT1 to increased nitro-oxidative stress in cardiomyocytes. We aimed to assess ... ...

Abstract	Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to be upregulated in humans with heart failure (HF) with or without diabetes. In vitro studies have linked SGLT1 to increased nitro-oxidative stress in cardiomyocytes. We aimed to assess the relation between left ventricular (LV) SGLT1 expression and the extent of nitro-oxidative stress in two non-diabetic rat models of chronic heart failure (HF) evoked by either pressure (TAC, n = 12) or volume overload (ACF, n = 12). Sham-operated animals (Sham-T and Sham-A, both n = 12) served as controls. Both TAC and ACF induced characteristic LV structural and functional remodeling. Western blotting revealed that LV SGLT1 protein expression was significantly upregulated in both HF models (both p < 0.01), whereas the phosphorylation of ERK1/2 was decreased only in ACF; AMPKα activity was significantly reduced in both models. The protein expression of the Nox4 NADPH oxidase isoform was increased in both TAC and ACF compared with respective controls (both p < 0.01), showing a strong positive correlation with SGLT1 expression (r = 0.855, p < 0.001; and r = 0.798, p = 0.001, respectively). Furthermore, SGLT1 protein expression positively correlated with the extent of myocardial nitro-oxidative stress in failing hearts assessed by 3-nitrotyrosin (r = 0.818, p = 0.006) and 4-hydroxy-2-nonenal (r = 0.733, p = 0.020) immunostaining. Therefore, LV SGLT1 protein expression was upregulated irrespective of the nature of chronic hemodynamic overload, and correlated significantly with the expression of Nox4 and with the level of myocardial nitro-oxidative stress, suggesting a pathophysiological role of SGLT1 in HF.
Keywords	NAD(P)H oxidase (H2O2-forming) ; cardiomyocytes ; diabetes ; heart failure ; hemodynamics ; phosphorylation ; protein synthesis ; rats ; symporters
Language	English
Dates of publication	2021-0726
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox10081190
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