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

Early Renal Denervation Attenuates Cardiac Dysfunction in Heart Failure With Preserved Ejection Fraction DOI Creative Commons
Jake E. Doiron, Zhen Li,

Xiaoman Yu

et al.

Journal of the American Heart Association, Journal Year: 2024, Volume and Issue: 13(4)

Published: Feb. 14, 2024

Background The renal sympathetic nervous system modulates systemic blood pressure, cardiac performance, and function. Pathological increases in nerve activity contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). We investigated effects denervation performed at early or late stages HFpEF progression. Methods Results Male ZSF1 obese rats were subjected radiofrequency (RF‐RDN) sham procedure either 8 weeks 20 age assessed for cardiovascular function, exercise capacity, cardiorenal fibrosis. Renal norepinephrine tyrosine hydroxylase staining quantify following RF‐RDN. In addition, injury, oxidative stress, inflammation, profibrotic biomarkers evaluated determine pathways associated RDN. RF‐RDN significantly reduced content both study cohorts. therapy attenuated dysfunction, fibrosis, improved endothelial‐dependent vascular reactivity. These improvements reductions injury markers, expression NLR family pyrin domain containing 3/interleukin 1β, mediators. failed exert beneficial when administered 20‐week‐old cohort. Conclusions Our data demonstrate that protects against disease progression part due attenuation fibrosis inflammation. contrast, renoprotective left ventricular functional lost was later results suggest RDN may be a viable treatment option during this inflammatory disease.

Language: Английский

Citations

8
iNOS contributes to heart failure with preserved ejection fraction through mitochondrial dysfunction and Akt S-nitrosylation DOI Creative Commons
Yongzheng Guo, Junjie Wen, An He

et al.

Journal of Advanced Research, Journal Year: 2022, Volume and Issue: 43, P. 175 - 186

Published: March 5, 2022

Despite the high morbidity and mortality of heart failure with preserved fraction (HFpEF), there are currently no effective therapies for this condition. Moreover, pathophysiological basis HFpEF remains poorly understood.The aim present study was to investigate role inducible nitric oxide synthase (iNOS) its underlying mechanism in a high-fat diet Nω-nitro-L-arginine methyl ester-induced mouse model.The selective iNOS inhibitor L-NIL used examine effects short-term inhibition, whereas long-term deficiency were evaluated using iNOS-null mice. Cardiac mitochondrial function, oxidative stress Akt S-nitrosylation then measured.The results demonstrated that both pharmacological inhibition knockout mitigated dysfunction, S-nitrosylation, leading an ameliorated phenotype In vitro, directly induced at cysteine 224 residues , stress, while inhibiting insulin-mediated glucose uptake myocytes.Altogether, findings suggested important development HFpEF, indicating may represent potential therapeutic strategy HFpEF.

Language: Английский

Citations

25
Mitochondrial DNA Is a Vital Driving Force in Ischemia-Reperfusion Injury in Cardiovascular Diseases DOI Creative Commons
Hui Liu, Xin Liu, Jingxin Zhou

et al.

Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 19

Published: May 17, 2022

According to the latest Global Burden of Disease Study, cardiovascular disease (CVD) is leading cause death, and ischemic heart stroke are death in approximately half CVD patients. In CVD, mitochondrial dysfunction following ischemia-reperfusion (I/R) injury results failure. The proper functioning oxidative phosphorylation (OXPHOS) life cycle cardiac mitochondria closely related DNA (mtDNA). Following myocardial I/R injury, activate multiple repair clearance mechanisms damaged mtDNA. When these insufficient restore structure function mtDNA, irreversible mtDNA damage occurs, mutations. Since mutations aggravate OXPHOS affect mitophagy, mutation accumulation leads leakage proteins outside mitochondria, inducing an innate immune response, aggravating need for external interventions stop or slow course. On other hand, released into circulation after can serve as a biomarker diagnosis prognosis. This article reviews pathogenic basis research findings leak-triggered response associated with summarizes therapeutic options that target

Language: Английский

Citations

23
CRIF1 attenuates doxorubicin-mediated mitochondrial dysfunction and myocardial senescence via regulating PXDN DOI Creative Commons
Lina Zhou,

Zhai Gui-lan,

Ge Tian

et al.

Aging, Journal Year: 2024, Volume and Issue: 16(6), P. 5567 - 5580

Published: March 15, 2024

Background: CR6-interacting factor 1 (CRIF1), a multifunctional protein that affects mitochondrial function and cell senescence, plays regulatory role in heart-related diseases. However, whether CRIF1 participates myocardial senescence by regulating remains unclear. Methods: Doxorubicin (DOX)-induced C57BL/6 mice to construct mouse model, the indicators including lactate dehydrogenase (LDH) Creatine kinase isoform MB (CK-MB) were assessed. The expression of was detected western blot. Myocardial pathological changes examined transthoracic echocardiography haematoxylin eosin (H&E) staining. Cell SA-β-gal JC-1 staining used detect membrane potential. Biochemical kits examine oxidative stress-related factors. Additionally, AC16 cardiomyocytes treated with DOX mimic cellular model vitro. activity counting kit-8 (CCK-8) assay. Co-immunoprecipitation (CO-IP) verify relationship between peroxidasin (PXDN). Results: significantly decreased DOX-induced senescent cells. Overexpression ameliorated dysfunction senescence. overexpression attenuated stress dysfunction. Consistently, also inhibited Moreover, verified bind PXDN expression. inhibitory effects on cells partly abolished Conclusions: protective against DOX-caused through downregulating PXDN.

Language: Английский

Citations

5
Current Understanding of Molecular Pathophysiology of Heart Failure With Preserved Ejection Fraction DOI Creative Commons

Heidi Budde,

Roua Hassoun,

Andreas Mügge

et al.

Frontiers in Physiology, Journal Year: 2022, Volume and Issue: 13

Published: July 7, 2022

Heart Failure (HF) is the most common cause of hospitalization in Western societies. HF a heterogeneous and complex syndrome that may result from any dysfunction systolic or diastolic capacity. Abnormal left ventricular function with impaired relaxation increased stiffness characteristic heart failure preserved ejection fraction (HFpEF). HFpEF accounts for more than 50% all cases HF. The prevalence increases age: around 1% those aged <55 years to >10% 70 over. Nearly patients have HFrEF other HFpEF/HFmrEF, mainly based on studies hospitalized patients. ESC Long-Term Registry, outpatient setting, reports 60% HFrEF, 24% HFmrEF, 16% HFpEF. To some extent, are female. closely associated co-morbidities, age, gender. Epidemiological evidence suggests highly represented older obese women proposed as ‘obese female phenotype’. While phenotype male phenotype. In addition, metabolic abnormalities hemodynamic perturbations appear greater impact then men ( Sorimachi et al., European J Fail, 2022 , 22). date, numerous clinical trials treatments produced disappointing results. This outcome “one size fits all” approach be inappropriate supports use tailored, personalized therapeutic strategies specific distinct phenotypes. important mediators cardiomyocytes, endothelial cells, extracellular matrix (ECM). physiological signal transduction networks respond dual challenges inflammatory oxidative stress major factors promote development pathologies. These signalling contribute diseases. Inhibition and/or attenuation these also delays onset disease. this review, we discuss molecular mechanisms responses inflammation emphasize nature contribution cells via stress.

Language: Английский

Citations

22
Cellular mechanisms and molecular pathways linking bitter taste receptor signalling to cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases DOI Open Access

Menizibeya O. Welcome,

D Dogo,

Nikos E. Mastorakis

et al.

Inflammopharmacology, Journal Year: 2022, Volume and Issue: 31(1), P. 89 - 117

Published: Dec. 6, 2022

Language: Английский

Citations

20
Inflammation in Heart Failure—Future Perspectives DOI Open Access
Alexandru Mircea Arvunescu, Ruxandra Florentina Ionescu, Sanda Maria Crețoiu

et al.

Journal of Clinical Medicine, Journal Year: 2023, Volume and Issue: 12(24), P. 7738 - 7738

Published: Dec. 17, 2023

Chronic heart failure is a terminal point of vast majority cardiac or extracardiac causes affecting around 1-2% the global population and more than 10% people above age 65. Inflammation persistently associated with chronic diseases, contributing in many cases to progression disease. Even low inflammatory state, past studies raised question whether inflammation constant condition, if it is, rather, triggered different amounts, according phenotype failure. By evaluating results clinical which focused on proinflammatory cytokines, this review aims identify ones that are independent risk factors for decompensation cardiovascular death. This assessed current evidence concerning activation cascade, but also future possible targets response modulation, can further impact course

Language: Английский

Citations

12
Anti-ageing interventions for the treatment of cardiovascular disease DOI Creative Commons
Mahmoud Abdellatif,

Sophie T Schmid,

Alexander Fuerlinger

et al.

Cardiovascular Research, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 22, 2024

As the global demographic landscape continues to shift towards an aged population, so does medical and socioeconomic burden of cardiovascular diseases. Indeed, ageing is one of, if not the, key risk factor for development However, there are currently no approved therapeutics that primarily target molecular cellular mechanisms underlying process itself. In this review, we present potential emerging anti-ageing strategies, including epigenetic rejuvenation, metabolic reprogramming, autophagy activation, as well senolytic anti-inflammatory therapies, in delaying or reversing age-related disorders, while considering sex differences. doing so, implicate processes pathogenesis several prevalent diseases, such atherosclerosis, hypertension, various types cardiomyopathies (including its hypertrophic, ischemic, dilated, diabetic, arrhythmogenic forms) heart failure, particularly with preserved ejection fraction. Finally, outline future challenges steps needed implementation these novel strategies clinical setting, aim challenging long-held notion a 'nonmodifiable'

Language: Английский

Citations

4
Trajectory of Cardiogenic Dementia: A New Perspective DOI Creative Commons

Nawaf Farhan Alrawili,

Hayder M. Al‐kuraishy, Ali I. Al‐Gareeb

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2025, Volume and Issue: 29(2)

Published: Jan. 1, 2025

ABSTRACT The functions of the heart and brain are closely linked essential to support human life by heart‐brain axis, which is a complex interconnection between brain. Also, cardiac function cerebral blood flow regulate brain's metabolism function. Therefore, deterioration may affect cognitive increase risk dementia. Cardiogenic dementia defined as due diseases such failure, myocardial infarction, atrial fibrillation. prevalence impairment in patients with failure was 29%. In addition, coronary artery disease (CAD) also associated development impairment. CAD reduction contractility reduced increased patients. Furthermore, infarction subsequent systemic haemodynamic instability promote progression cardiogenic These findings indicated that many implicated Nevertheless, underlying mechanism for not fully elucidated. Consequently, this review aims discuss potential mechanisms involved pathogenesis

Language: Английский

Citations

0
Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction DOI Creative Commons
Thássio Mesquita, Rodrigo Miguel‐dos‐Santos, Weixin Liu

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 30, 2025

Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal male HFpEF hearts. Genetic suppression of FoxO1 alters intercellular communication between cardiomyocytes fibroblasts, alleviates diastolic relaxation, reduces arrhythmias. Targeted downregulation activated fibroblasts fibrosis, blunts arrhythmogenesis improves function HFpEF. These results not only implicate lusitropy also demonstrate that pro-fibrotic remodeling cardiomyocyte-fibroblast can be corrected, constituting an alternative therapeutic strategy for authors show by improving communication. findings suggest targeting may serve anti-arrhythmic

Language: Английский

Citations

0