Diabetes mellitus aggravates myocardial inflammation and oxidative stress in aortic stenosis: a mechanistic link to HFpEF features.

IF 8.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Melissa Herwig, Marcel Sieme, Andrea Kovács, Muchtiar Khan, Andreas Mügge, Wolfgang E Schmidt, Ferhat Elci, Shan Sasidharan, Peter Haldenwang, Jan Wintrich, Benjamin Sasko, Ibrahim Akin, Máthé Domokos, Francesco Paneni, Ibrahim El-Battrawy, Zoltán V Varga, Francisca Saraiva, Adelino F Leite-Moreira, Péter Ferdinandy, Loek van Heerebeek, Inês Falcão-Pires, Nazha Hamdani
{"title":"Diabetes mellitus aggravates myocardial inflammation and oxidative stress in aortic stenosis: a mechanistic link to HFpEF features.","authors":"Melissa Herwig, Marcel Sieme, Andrea Kovács, Muchtiar Khan, Andreas Mügge, Wolfgang E Schmidt, Ferhat Elci, Shan Sasidharan, Peter Haldenwang, Jan Wintrich, Benjamin Sasko, Ibrahim Akin, Máthé Domokos, Francesco Paneni, Ibrahim El-Battrawy, Zoltán V Varga, Francisca Saraiva, Adelino F Leite-Moreira, Péter Ferdinandy, Loek van Heerebeek, Inês Falcão-Pires, Nazha Hamdani","doi":"10.1186/s12933-025-02748-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Patients diagnosed with both aortic stenosis (AS) and diabetes mellitus (DM) encounter a distinctive set of challenges due to the interplay between these two conditions. This study aimed to investigate the effects of DM on the left ventricle in AS patients, specifically focusing on the inflammatory response, oxidative stress, and their implications for cardiomyocyte function, titin phosphorylation, and the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway.</p><p><strong>Methods and results: </strong>Left ventricular myocardial biopsies (in total: n = 28) were obtained from patients with diabetic AS (n = 11) and compared with those from non-diabetic AS patients (n = 17). Enzyme-linked immunosorbent assay (ELISA) demonstrated significantly elevated levels of pro-inflammatory mediators, including high mobility group box protein 1 (HMGB1) and calprotectin, as well as receptors associated with the inflammatory response, such as Toll-like receptor 2 (TLR2), 4 (TLR4), and receptor for advanced glycation endproducts (RAGE). These were correlated with an enhanced NOD-like receptor protein 3 (NLRP3) inflammasome and the release of interleukins (IL) 1, 6, and 18 in diabetic AS patients compared to their non-diabetic counterparts. Additionally, in the diabetic AS cohort, there was an increase in oxidative stress markers (hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), 3-nitrotyrosine, lipid peroxidation (LPO), oxidative glutathione (GSSG)/reduced glutathione (GSH) ratio) within the myocardium and mitochondria, accompanied by impaired NO-sGC-cGMP-PKG signaling, decreased titin phosphorylation, and increased passive stiffness (F<sub>passive</sub>) of cardiomyocytes relative to non-diabetic AS patients. In vitro anti-inflammatory treatment with an IL-6 inhibitor and antioxidant treatment with GSH effectively normalized the elevated F<sub>passive</sub> observed in AS patients with DM to levels comparable to the non-diabetic group. Furthermore, treatment with PKG and the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin also resulted in a reduction of F<sub>passive</sub> in cardiomyocytes from diabetic AS patients, although not to the levels observed in non-diabetic AS patients.</p><p><strong>Conclusion: </strong>DM exacerbates inflammation and oxidative stress in AS patients, leading to impaired NO-sGC-cGMP-PKG signaling and increased cardiomyocyte F<sub>passive</sub>. These conditions are reminiscent of the pathophysiology of heart failure with preserved ejection fraction (HFpEF). These alterations can be ameliorated through anti-inflammatory and antioxidant therapies, indicating potential therapeutic strategies for diabetic patients suffering from AS.</p>","PeriodicalId":9374,"journal":{"name":"Cardiovascular Diabetology","volume":"24 1","pages":"203"},"PeriodicalIF":8.5000,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070770/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cardiovascular Diabetology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12933-025-02748-y","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Patients diagnosed with both aortic stenosis (AS) and diabetes mellitus (DM) encounter a distinctive set of challenges due to the interplay between these two conditions. This study aimed to investigate the effects of DM on the left ventricle in AS patients, specifically focusing on the inflammatory response, oxidative stress, and their implications for cardiomyocyte function, titin phosphorylation, and the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway.

Methods and results: Left ventricular myocardial biopsies (in total: n = 28) were obtained from patients with diabetic AS (n = 11) and compared with those from non-diabetic AS patients (n = 17). Enzyme-linked immunosorbent assay (ELISA) demonstrated significantly elevated levels of pro-inflammatory mediators, including high mobility group box protein 1 (HMGB1) and calprotectin, as well as receptors associated with the inflammatory response, such as Toll-like receptor 2 (TLR2), 4 (TLR4), and receptor for advanced glycation endproducts (RAGE). These were correlated with an enhanced NOD-like receptor protein 3 (NLRP3) inflammasome and the release of interleukins (IL) 1, 6, and 18 in diabetic AS patients compared to their non-diabetic counterparts. Additionally, in the diabetic AS cohort, there was an increase in oxidative stress markers (hydrogen peroxide (H2O2), 3-nitrotyrosine, lipid peroxidation (LPO), oxidative glutathione (GSSG)/reduced glutathione (GSH) ratio) within the myocardium and mitochondria, accompanied by impaired NO-sGC-cGMP-PKG signaling, decreased titin phosphorylation, and increased passive stiffness (Fpassive) of cardiomyocytes relative to non-diabetic AS patients. In vitro anti-inflammatory treatment with an IL-6 inhibitor and antioxidant treatment with GSH effectively normalized the elevated Fpassive observed in AS patients with DM to levels comparable to the non-diabetic group. Furthermore, treatment with PKG and the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin also resulted in a reduction of Fpassive in cardiomyocytes from diabetic AS patients, although not to the levels observed in non-diabetic AS patients.

Conclusion: DM exacerbates inflammation and oxidative stress in AS patients, leading to impaired NO-sGC-cGMP-PKG signaling and increased cardiomyocyte Fpassive. These conditions are reminiscent of the pathophysiology of heart failure with preserved ejection fraction (HFpEF). These alterations can be ameliorated through anti-inflammatory and antioxidant therapies, indicating potential therapeutic strategies for diabetic patients suffering from AS.

糖尿病加重主动脉瓣狭窄的心肌炎症和氧化应激:与HFpEF特征的机制联系
背景:被诊断为主动脉瓣狭窄(AS)和糖尿病(DM)的患者由于这两种疾病之间的相互作用而遇到了一系列独特的挑战。本研究旨在探讨DM对AS患者左心室的影响,特别关注炎症反应、氧化应激及其对心肌细胞功能、titin磷酸化和一氧化氮(NO)-可溶性鸟苷环化酶(sGC)-环鸟苷单磷酸(cGMP)-蛋白激酶G (PKG)信号通路的影响。方法与结果:对11例糖尿病性AS患者(n = 28)进行左心室心肌活检,并与17例非糖尿病性AS患者(n = 17)进行比较。酶联免疫吸附试验(ELISA)显示,促炎介质水平显著升高,包括高迁移率组盒蛋白1 (HMGB1)和钙保护蛋白,以及与炎症反应相关的受体,如toll样受体2 (TLR2)、4 (TLR4)和晚期糖基化终产物受体(RAGE)。与非糖尿病AS患者相比,这些与增强的nod样受体蛋白3 (NLRP3)炎性体和白细胞介素(IL) 1、6和18的释放相关。此外,在糖尿病AS队列中,心肌和线粒体内氧化应激标志物(过氧化氢(H2O2), 3-硝基酪氨酸,脂质过氧化(LPO),氧化谷胱甘肽(GSSG)/还原性谷胱甘肽(GSH)比率)增加,伴有NO-sGC-cGMP-PKG信号受损,titin磷酸化降低,心肌细胞被动僵硬(Fpassive)增加相对于非糖尿病AS患者。用IL-6抑制剂进行体外抗炎治疗和用谷胱甘肽进行抗氧化治疗,可有效地将AS合并DM患者中观察到的升高的Fpassive正常化至与非糖尿病组相当的水平。此外,用PKG和钠-葡萄糖共转运蛋白2 (SGLT2)抑制剂恩帕列净治疗也导致糖尿病AS患者心肌细胞中Fpassive的降低,尽管没有达到非糖尿病AS患者的水平。结论:糖尿病加重AS患者的炎症和氧化应激,导致NO-sGC-cGMP-PKG信号通路受损,心肌细胞Fpassive升高。这些情况让人想起保留射血分数(HFpEF)心力衰竭的病理生理学。这些改变可以通过抗炎和抗氧化治疗得到改善,这为患有AS的糖尿病患者提供了潜在的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信