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

IF 8.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Simin Delalat, Innas Sultana, Hersh Osman, Marcel Sieme, Saltanat Zhazykbayeva, Melissa Herwig, Heidi Budde, Árpád Kovács, Mustafa Kaçmaz, Eda Göztepe, Natalie Borgmann, Gelareh Shahriari, Benjamin Sasko, Jan Wintrich, Peter Haldenwang, Wolfgang E Schmidt, Wiebke Fenske, Muchtiar Khan, Kornelia Jaquet, Andreas Mügge, Domokos Máthé, Viktória E Tóth, Zoltán V Varga, Péter Ferdinandy, Ibrahim El-Battrawy, Loek van Heerebeek, Nazha Hamdani
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引用次数: 0

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, and is characterized by dysfunctions associated with metabolic, inflammatory, and oxidative stress pathways. Despite HFpEF being the most prevalent heart failure phenotype in patients with T2DM, its underlying pathophysiological mechanisms remain inadequately elucidated.

Objective: This study aims to investigate the effects of diabetes mellitus on myocardial inflammation, oxidative stress, and protein quality control (PQC) mechanisms in HFpEF, with particular emphasis on insulin signaling, autophagy, and chaperone-mediated stress responses.

Methods: We conducted an analysis of left ventricular myocardial tissue from HFpEF patients, both with and without diabetes, employing a range of molecular, biochemical, and functional assays. The passive stiffness of cardiomyocytes (Fpassive) was assessed in demembranated cardiomyocytes before and after implementing treatments aimed at reducing inflammation (IL-6 inhibition), oxidative stress (Mito-TEMPO), and enhancing PQC (HSP27, HSP70). Inflammatory markers (NF-κB, IL-6, TNF-α, ICAM-1, VCAM-1, NLRP3), oxidative stress markers (ROS, GSH/GSSG ratio, lipid peroxidation), and components of signaling pathways (PI3K/AKT/mTOR, AMPK, MAPK, and PKG) were evaluated using western blotting, immunofluorescence, and ELISA techniques.

Results: Hearts from diabetic HFpEF patients exhibited significantly heightened inflammation, characterized by the upregulation of NF-κB, IL-6, and the NLRP3 inflammasome. This increase in inflammation was accompanied by elevated oxidative stress, diminished nitric oxide (NO) bioavailability, and impaired activation of the NO-sGC-cGMP-PKG signaling pathway. Notably, dysregulation of insulin signaling was observed, as indicated by decreased AKT phosphorylation and impaired autophagy regulation mediated by AMPK and mTOR. Additionally, PQC dysfunction was evidenced by reduced expression levels of HSP27 and HSP70, which correlated with increased cardiomyocyte passive stiffness. Targeted therapeutic interventions effectively reduced Fpassive, with IL-6 inhibition, Mito-TEMPO, and HSP administration leading to improvements in cardiomyocyte mechanical properties.

Conclusion: The findings of this study elucidate a mechanistic relationship among diabetes, inflammation, oxidative stress, and PQC impairment in the context of HFpEF. Therapeutic strategies that target these dysregulated pathways, including IL-6 inhibition, mitochondrial antioxidants, and chaperone-mediated protection, may enhance myocardial function in HFpEF patients with T2DM. Addressing these molecular dysfunctions could facilitate the development of novel interventions specifically tailored to the diabetic HFpEF population.

糖尿病HFpEF中炎症失调、氧化应激和蛋白质质量控制:揭示机制和治疗靶点。
背景:2型糖尿病(T2DM)是心血管疾病的重要危险因素,尤其是保留射血分数的心力衰竭(HFpEF)。HFpEF主要影响老年人和女性,其特征是与代谢、炎症和氧化应激途径相关的功能障碍。尽管HFpEF是T2DM患者中最常见的心力衰竭表型,但其潜在的病理生理机制仍未充分阐明。目的:本研究旨在探讨糖尿病对HFpEF心肌炎症、氧化应激和蛋白质量控制(PQC)机制的影响,特别是胰岛素信号、自噬和伴侣介导的应激反应。方法:我们对患有和不患有糖尿病的HFpEF患者的左心室心肌组织进行了分析,采用了一系列分子、生化和功能分析。在实施旨在减少炎症(IL-6抑制)、氧化应激(Mito-TEMPO)和增强PQC (HSP27、HSP70)的治疗前后,对脱膜心肌细胞进行心肌细胞被动僵硬(Fpassive)的评估。采用western blotting、免疫荧光和ELISA技术评估炎症标志物(NF-κB、IL-6、TNF-α、ICAM-1、VCAM-1、NLRP3)、氧化应激标志物(ROS、GSH/GSSG比值、脂质过氧化)和信号通路组分(PI3K/AKT/mTOR、AMPK、MAPK和PKG)。结果:糖尿病HFpEF患者心脏炎症明显升高,表现为NF-κB、IL-6和NLRP3炎症小体上调。这种炎症的增加伴随着氧化应激升高、一氧化氮(NO)生物利用度降低以及NO- sgc - cgmp - pkg信号通路的激活受损。值得注意的是,胰岛素信号通路失调,AKT磷酸化降低,AMPK和mTOR介导的自噬调节受损。此外,PQC功能障碍的证据是HSP27和HSP70的表达水平降低,这与心肌细胞被动僵硬度增加有关。有针对性的治疗干预有效地降低了Fpassive,通过抑制IL-6, Mito-TEMPO和HSP管理导致心肌细胞力学性能的改善。结论:本研究结果阐明了HFpEF背景下糖尿病、炎症、氧化应激和PQC损伤之间的机制关系。针对这些失调通路的治疗策略,包括IL-6抑制、线粒体抗氧化剂和伴侣介导的保护,可能会增强HFpEF合并T2DM患者的心肌功能。解决这些分子功能障碍可以促进开发专门针对糖尿病HFpEF人群的新型干预措施。
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来源期刊
Cardiovascular Diabetology
Cardiovascular Diabetology 医学-内分泌学与代谢
CiteScore
12.30
自引率
15.10%
发文量
240
审稿时长
1 months
期刊介绍: Cardiovascular Diabetology is a journal that welcomes manuscripts exploring various aspects of the relationship between diabetes, cardiovascular health, and the metabolic syndrome. We invite submissions related to clinical studies, genetic investigations, experimental research, pharmacological studies, epidemiological analyses, and molecular biology research in this field.
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