Dysregulated inflammation, oxidative stress, and protein quality control in diabetic HFpEF: unraveling mechanisms and therapeutic targets DOI Creative Commons

Simin Delalat,

Innas Sultana,

Hersh Osman

et al.

Cardiovascular Diabetology, Journal Year: 2025, Volume and Issue: 24(1)

Published: May 14, 2025

Abstract Background Type 2 diabetes mellitus (T2DM) represents a significant risk factor for cardiovascular disease, particularly heart failure with preserved ejection fraction (HFpEF). HFpEF predominantly affects elderly individuals and women, is characterized by dysfunctions associated metabolic, inflammatory, oxidative stress pathways. Despite being the most prevalent phenotype in patients T2DM, its underlying pathophysiological mechanisms remain inadequately elucidated. Objective This study aims to investigate effects of on myocardial inflammation, stress, protein quality control (PQC) HFpEF, particular emphasis insulin signaling, autophagy, chaperone-mediated responses. Methods We conducted an analysis left ventricular tissue from patients, both without diabetes, employing range molecular, biochemical, functional assays. The passive stiffness cardiomyocytes (Fpassive) was assessed demembranated before after implementing treatments aimed at reducing inflammation (IL-6 inhibition), (Mito-TEMPO), enhancing PQC (HSP27, HSP70). Inflammatory markers (NF-κB, IL-6, TNF-α, ICAM-1, VCAM-1, NLRP3), (ROS, GSH/GSSG ratio, lipid peroxidation), components signaling pathways (PI3K/AKT/mTOR, AMPK, MAPK, PKG) were evaluated using western blotting, immunofluorescence, ELISA techniques. Results Hearts diabetic exhibited significantly heightened upregulation NF-κB, NLRP3 inflammasome. increase accompanied elevated diminished nitric oxide (NO) bioavailability, impaired activation NO-sGC-cGMP-PKG pathway. Notably, dysregulation observed, as indicated decreased AKT phosphorylation autophagy regulation mediated AMPK mTOR. Additionally, dysfunction evidenced reduced expression levels HSP27 HSP70, which correlated increased cardiomyocyte stiffness. Targeted therapeutic interventions effectively Fpassive, IL-6 inhibition, Mito-TEMPO, HSP administration leading improvements mechanical properties. Conclusion findings this elucidate mechanistic relationship among impairment context HFpEF. Therapeutic strategies that target these dysregulated pathways, including mitochondrial antioxidants, protection, may enhance function T2DM. Addressing molecular could facilitate development novel specifically tailored population. Graphical abstract

Language: Английский

Association between neutrophil percentage-to-albumin ratio (NPAR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and long-term mortality in community-dwelling adults with heart failure: evidence from US NHANES 2005–2016 DOI Creative Commons
Chia‐Chen Wu, Chia-Hui Wu, Chien‐Ho Lee

et al.

BMC Cardiovascular Disorders, Journal Year: 2023, Volume and Issue: 23(1)

Published: June 21, 2023

Abstract Background Heart failure (HF) continues to be the major cause of hospitalizations. Despite numerous significant therapeutic progress, mortality rate HF is still high. This longitudianl cohort study aimed investigate associations between hematologic inflammatory indices neutrophil percentage-to-albumin ratio (NPAR), neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and all-cause in community-dwelling adults with HF. Methods Adults aged 20 older US National Health Nutrition Examination Survey (NHANES) database 2005–2016 were included followed through end 2019. Univariate multivariable Cox regression analyses performed determine three biomarkers mortality. The receiver operating characteristics (ROC) curve analysis was conducted evaluate their predictive performance on Results A total 1,207 subjects included, representing a population 4,606,246 US. median follow-up duration 66.0 months. After adjustment, highest quartile NPAR (aHR = 1.81, 95%CI: 1.35, 2.43) NLR 1.59, 1.18, 2.15) significantly associated increased risk compared lowest during Elevated PLR not risk. area under ROC (AUC) NPAR, NLR, predicting deaths 0.61 (95%CI: 0.58, 0.65), 0.64 0.6, 0.67), 0.58 (95%CI:0.55, 0.61), respectively. Conclusions In conclusion, elevated but are independently among individuals However, alone low.

Language: Английский

Citations

50
Inflammation in Obesity-Related HFpEF DOI Creative Commons

Subodh Verma,

Mark C. Petrie, Barry A. Borlaug

et al.

Journal of the American College of Cardiology, Journal Year: 2024, Volume and Issue: 84(17), P. 1646 - 1662

Published: Aug. 30, 2024

Inflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved failure-related symptoms, physical limitations, exercise function, reduced levels C-reactive protein (CRP), a biomarker inflammation, body weight in participants HFpEF. However, neither prevalence nor clinical characteristics patients who have various magnitudes inflammation context HFpEF been well described. Furthermore, whether beneficial effects on HF efficacy endpoints Program are modified by baseline has not fully established. Finally, relationship between reduction changes CRP across defined.

Language: Английский

Citations

19
Chronic low‐grade inflammation in heart failure with preserved ejection fraction DOI Creative Commons
Thássio Mesquita, Yen‐Nien Lin, Ahmed Ibrahim

et al.

Aging Cell, Journal Year: 2021, Volume and Issue: 20(9)

Published: Aug. 12, 2021

Abstract Heart failure (HF) with preserved ejection fraction (HFpEF) is currently the predominant form of HF a dramatic increase in risk age. Low‐grade inflammation, as occurs aging (termed “inflammaging”), common feature HFpEF pathology. Suppression proinflammatory pathways has been associated attenuated disease severity and better outcomes. From this perspective, inflammasome signaling plays central role mediating chronic inflammation cardiovascular progression. However, causal link between inflammasome‐immune axis on age‐dependent progression remains conjectural. In review, we summarize current understanding inflammatory cardiac function decline. We will also evaluate recent advances evidence regarding pathway pathophysiology HFpEF, special attention to signaling.

Language: Английский

Citations

59
Colchicine alleviates inflammation and improves diastolic dysfunction in heart failure rats with preserved ejection fraction DOI Creative Commons
Song Shen,

Junfeng Duan,

Jiaxin Hu

et al.

European Journal of Pharmacology, Journal Year: 2022, Volume and Issue: 929, P. 175126 - 175126

Published: June 30, 2022

Several studies have reported that colchicine attenuates cardiac inflammation and improves function in myocardial infarction atrial fibrillation. However, no study has investigated its effect on heart failure with preserved ejection fraction (HFpEF). Hence, this aimed to assess efficacy a high salt diet (HSD)-induced HFpEF rat model.A hypertension-induced model was created by treating Dahl/SS salt-sensitive rats an HSD for 6 weeks. Colchicine given via gavage daily as treatment. Cardiac were assessed using echocardiography, histology, ELISA. Furthermore, the expression levels of NLRP3 NF-κB signaling pathways examined.Treatment increased survival attenuated dysfunction, indicated decreased echocardiographic E/A ratio longer exercise endurance along reduced ventricular fibrosis remodeling HSD-induced Dahl rats. The treatment also oxidative stress inflammatory cell infiltration, inferred from lower mRNA expressions TNFα CCL2 well protein pathways.The findings signify plays crucial role alleviating systemic activation attenuating dysfunction model. Colchicine, therefore, holds therapeutic potential further clinical applications.

Language: Английский

Citations

42
Endothelial cell dysfunction in cardiac disease: driver or consequence? DOI Creative Commons
Jules D. Allbritton‐King, Guillermo Garcı́a-Cardeña

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Oct. 25, 2023

The vascular endothelium is a multifunctional cellular system which directly influences blood components and cells within the vessel wall in given tissue. Importantly, this interface undergoes critical phenotypic changes response to various biochemical hemodynamic stimuli, driving several developmental pathophysiological processes. Multiple studies have indicated central role of initiation, progression, clinical outcomes cardiac disease. In review we synthesize current understanding endothelial function dysfunction as mediators cardiomyocyte phenotype setting distinct pathologies; outline existing

Language: Английский

Citations

28
Sodium-glucose cotransporter 2 inhibitors, inflammation, and heart failure: a two-sample Mendelian randomization study DOI Creative Commons
Wenqin Guo, Lingyue Zhao, Weichao Huang

et al.

Cardiovascular Diabetology, Journal Year: 2024, Volume and Issue: 23(1)

Published: April 2, 2024

Abstract Background Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are increasingly recognized for their role in reducing the risk and improving prognosis of heart failure (HF). However, precise mechanisms involved remain to be fully delineated. Evidence points potential anti-inflammatory pathway mitigating HF. Methods A two-sample, two-step Mendelian Randomization (MR) approach was employed assess correlation between SGLT-2 inhibition HF, along with mediating effects inflammatory biomarkers this relationship. MR is an analytical methodology that leverages single nucleotide polymorphisms as instrumental variables infer causal inferences exposures outcomes within observational data frameworks. Genetic variants correlated expression SLC5A2 gene glycated hemoglobin levels (HbA1c) were selected using datasets from Genotype-Tissue Expression project eQTLGen consortium. The Genome-wide association study (GWAS) 92 obtained two datasets, which included 14,824 575,531 individuals European ancestry, respectively. GWAS HF derived a meta-analysis combined 26 cohorts, including 47,309 cases 930,014 controls. Odds ratios (ORs) 95% confidence interval (CI) calculated per 1 unit change HbA1c. Results Genetically predicted associated reduced (OR 0.42 [95% CI 0.30–0.59], P < 0.0001). Of studied, (C-X-C motif chemokine ligand 10 [CXCL10] leukemia inhibitory factor) both Multivariable analysis revealed CXCL10 primary cytokine related (MIP = 0.861, MACE 0.224, FDR-adjusted 0.0844). effect on mediated by 17.85% total (95% [3.03%–32.68%], 0.0183). Conclusions This provides genetic evidence supporting beneficial impact emerged mediator, offering novel intervention treatment. Graphical

Language: Английский

Citations

14
Systemic aging fuels heart failure: Molecular mechanisms and therapeutic avenues DOI Creative Commons

Zhuyubing Fang,

Umar Raza,

Jia Song

et al.

ESC Heart Failure, Journal Year: 2024, Volume and Issue: unknown

Published: July 22, 2024

Abstract Systemic aging influences various physiological processes and contributes to structural functional decline in cardiac tissue. These alterations include an increased incidence of left ventricular hypertrophy, a diastolic function, atrial dilation, fibrillation, myocardial fibrosis amyloidosis, elevating susceptibility chronic heart failure (HF) the elderly. Age‐related dysfunction stems from prolonged exposure genomic, epigenetic, oxidative, autophagic, inflammatory regenerative stresses, along with accumulation senescent cells. Concurrently, age‐related changes vascular system, attributed endothelial dysfunction, arterial stiffness, impaired angiogenesis, oxidative stress inflammation, impose additional strain on heart. Dysregulated mechanosignalling nitric oxide signalling play critical roles associated HF. Metabolic drives intricate shifts glucose lipid metabolism, leading insulin resistance, mitochondrial within cardiomyocytes. contribute contractility, ultimately propelling low‐grade conjunction senescence‐associated secretory phenotype, aggravates age by promoting immune cell infiltration into myocardium, fostering This is further exacerbated comorbidities like coronary artery disease (CAD), atherosclerosis, hypertension, obesity, diabetes kidney (CKD). CAD atherosclerosis induce ischaemia adverse remodelling, while hypertension hypertrophy fibrosis. Obesity‐associated inflammation dyslipidaemia create profibrotic environment, whereas diabetes‐related metabolic disturbances impair function. CKD‐related fluid overload, electrolyte imbalances uraemic toxins exacerbate HF through systemic neurohormonal renin‐angiotensin‐aldosterone system (RAAS) activation. Recognizing as modifiable process has opened avenues target both lifestyle interventions therapeutics. Exercise, known for its antioxidant effects, can partly reverse pathological remodelling elderly countering linked HF, such senescence declining cardiomyocyte regeneration. Dietary plant‐based ketogenic diets, caloric restriction macronutrient supplementation are instrumental maintaining energy balance, reducing adiposity addressing micronutrient Therapeutic advancements targeting underway. Key approaches senomorphics senolytics limit senescence, antioxidants stress, anti‐inflammatory drugs interleukin (IL)‐1β inhibitors, rejuvenators nicotinamide riboside, resveratrol sirtuin (SIRT) activators autophagy enhancers metformin sodium‐glucose cotransporter 2 (SGLT2) all which offer potential preserving function alleviating burden.

Language: Английский

Citations

10
Role of pyroptosis in diabetic cardiomyopathy: an updated review DOI Creative Commons
Gan Wang, Tianyi Ma, Kang Huang

et al.

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 5, 2024

Diabetic cardiomyopathy (DCM), one of the common complications diabetes, presents as a specific with anomalies in structure and function heart. With increasing prevalence DCM has high morbidity mortality worldwide. Recent studies have found that pyroptosis, programmed cell death accompanied by an inflammatory response, exacerbates growth genesis DCM. These provide theoretical basis for exploring potential treatment Therefore, this review aims to summarise possible mechanisms which pyroptosis promotes development well relevant targeting DCM, focusing on molecular NLRP3 inflammasome-mediated different cellular pathways associated effects occurring cells drugs inflammasome/pyroptosis This might fresh perspective foundation therapeutic agents

Language: Английский

Citations

9
Diabetic Cardiomyopathy: 2023 Update by the International Multidisciplinary Board of Experts DOI
Ashot Avagimyan, Federica Fogacci, Nana Pogosova

et al.

Current Problems in Cardiology, Journal Year: 2023, Volume and Issue: 49(1), P. 102052 - 102052

Published: Aug. 26, 2023

Language: Английский

Citations

20
Discovery of a novel 1,3,4-oxadiazol-2-one-based NLRP3 inhibitor as a pharmacological agent to mitigate cardiac and metabolic complications in an experimental model of diet-induced metaflammation DOI Creative Commons
Simone Gastaldi, Carmine Rocca, Eleonora Gianquinto

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 257, P. 115542 - 115542

Published: June 3, 2023

Inspired by the recent advancements in understanding binding mode of sulfonylurea-based NLRP3 inhibitors to sensor protein, we developed new replacing central sulfonylurea moiety with different heterocycles. Computational studies evidenced that some designed compounds were able maintain important interaction within NACHT domain target protein similarly most active inhibitors. Among studied compounds, 1,3,4-oxadiazol-2-one derivative 5 (INF200) showed promising results being prevent NLRP3-dependent pyroptosis triggered LPS/ATP and LPS/MSU 66.3 ± 6.6% 61.6 11.5% reduce IL-1β release (35.5 8.8% μM) at 10 μM human macrophages. The selected compound INF200 (20 mg/kg/day) was then tested an vivo rat model high-fat diet (HFD)-induced metaflammation evaluate its beneficial cardiometabolic effects. significantly counteracted HFD-dependent "anthropometric" changes, improved glucose lipid profiles, attenuated systemic inflammation biomarkers cardiac dysfunction (particularly BNP). Hemodynamic evaluation on Langendorff indicate limited myocardial damage-dependent ischemia/reperfusion injury (IRI) improving post-ischemic systolic recovery attenuating contracture, infarct size, LDH release, thus reversing exacerbation obesity-associated damage. Mechanistically, hearts, IFN200 reduced IRI-dependent activation, inflammation, oxidative stress. These highlight potential novel inhibitor, INF200, ability reverse unfavorable cardio-metabolic associated obesity.

Language: Английский

Citations

18