Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study.

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-08-30 Epub Date: 2024-07-29 DOI:10.1161/CIRCRESAHA.124.324272
Khaled Z Abd-Elmoniem, Jehad H Edwan, Katrina B Dietsche, Alfredo Villalobos-Perez, Nour Shams, Jatin Matta, Leilah Baumgarten, Waleed N Qaddumi, Sydney A Dixon, Aruba Chowdhury, Michael Stagliano, Lilian Mabundo, Annemarie Wentzel, Colleen Hadigan, Ahmed M Gharib, Stephanie T Chung
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Abstract

Background: Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings.

Methods: Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate.

Results: Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; P=0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; P<0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; P=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells.

Conclusions: Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.

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青年 2 型糖尿病患者的内皮功能障碍:临床转化研究
背景:青年期发病的 2 型糖尿病(Y-T2D)与冠状动脉粥样硬化性疾病的风险增加有关,但在这一人群中最早出现病理特征的时间和心脏内皮功能障碍的证据尚未得到评估。磁共振成像功能成像可在没有经典风险因素(严重高血糖、高血压和高脂血症)的情况下,早期直接检测出内皮功能障碍。通过心脏磁共振成像功能成像,我们评估了确诊≤5 年的 Y-T2D 青壮年与年龄匹配的健康同龄人的外周和冠状动脉内皮结构和功能。我们分离并鉴定了血浆衍生的小细胞外囊泡,评估了它们对健康人冠状动脉内皮细胞炎症和信号传导生物标志物的影响,以验证成像结果:方法:使用 3.0T 磁共振成像仪测量基线和等长手握运动时的右冠状动脉壁厚度、冠状动脉血流介导的扩张和肱动脉血流介导的扩张。用 Y-T2D 血浆衍生的小细胞外囊泡处理人冠状动脉内皮细胞。蛋白质表达通过 Western 印迹分析进行测量,氧化应激通过氧化还原敏感探针二氢乙锭进行测量,一氧化氮水平通过 4-氨基-5-甲基氨基-2',7'-二氟荧光素二乙酸酯进行测量:与健康人(16 人)相比,Y-T2D(20 人)的血红蛋白 A1c 和高敏 C 反应蛋白较高,但总胆固醇和 LDL(低密度脂蛋白)胆固醇相似。Y-T2D的冠状动脉壁厚度更大(1.33±0.13 mm对1.22±0.13 mm;P=0.04),内皮功能受损:冠状动脉血流介导的扩张(-3.1±15.5%对15.9±17.3%;PP=0.001)。Y-T2D血浆衍生的小细胞外囊泡降低了磷酸化内皮一氧化氮合酶的表达和一氧化氮水平,增加了活性氧的产生,升高了ICAM(细胞间粘附分子)介导的人冠状动脉内皮细胞炎症通路:Y-T2D患者的冠状动脉和肱动脉内皮功能障碍在确诊后5年内十分明显,且没有严重的高血糖或血脂异常。血浆源性小细胞外囊泡诱导内皮功能障碍标志物,这证实了亚临床冠状动脉粥样硬化加速是Y-T2D的早期特征:URL: https://www.clinicaltrials.gov; Unique identifier:NCT02830308。
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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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