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Prostacyclin Synthase Deficiency Leads to Exacerbation or Occurrence of Endothelium-Dependent Contraction and Causes Cardiovascular Disorders Mainly via the Non-TxA2 Prostanoids/TP Axis. 前列环素合成酶缺乏症主要通过非 TxA2 类前列腺素/TP 轴导致内皮依赖性收缩加剧或发生,并引发心血管疾病。
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-30 Epub Date: 2024-07-31 DOI: 10.1161/CIRCRESAHA.124.324924
Jiahui Ge, Yingbi Zhou, Hui Li, Ruhui Zeng, Kaiqi Xie, Jing Leng, Xijian Chen, Gang Yu, Xinya Shi, Yineng Xu, Dong He, Pi Guo, Yongyin Zhou, Hongjun Luo, Wenhong Luo, Bin Liu
<p><strong>Background: </strong>Prostaglandin I<sub>2</sub> synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. Prostaglandin I<sub>2</sub> production and EDC may be enhanced in diseases such as hypertension. However, how PGIS (prostaglandin I<sub>2</sub> synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown.</p><p><strong>Methods: </strong>Experiments were performed with wild-type, <i>Pgis</i> knockout (<i>Pgis</i><sup><i>-</i>/<i>-</i></sup>) and <i>Pgis</i>/thromboxane-prostanoid receptor gene (<i>Tp</i>) double knockout (<i>Pgis</i><sup><i>-</i>/<i>-</i></sup><i>Tp</i><sup><i>-</i>/<i>-</i></sup>) mice and <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice transplanted with unfractionated wild-type or <i>Cox-1</i><sup><i>-</i>/<i>-</i></sup> bone marrow cells, as well as human umbilical arteries. COX-derived prostanoids were measured by high-performance liquid chromatography-mass spectrometry. Vasomotor responses of distinct types of arteries were assessed by isometric force measurement. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored.</p><p><strong>Results: </strong>PGF<sub>2α</sub>, PGE<sub>2</sub>, and a trace amount of PGD<sub>2</sub>, but not thromboxane A<sub>2</sub> (TxA<sub>2</sub>), were produced in response to acetylcholine in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> or PGIS-inhibited arteries. PGIS deficiency resulted in exacerbation or occurrence of EDC ex vivo and in vivo. Endothelium-dependent hyperpolarization was unchanged, but phosphorylation levels of eNOS (endothelial nitric oxide synthase) at Ser1177 and Thr495 were altered and NO production and the NO-dependent relaxation evoked by acetylcholine were remarkably reduced in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> aortas. <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice developed high blood pressure and vascular remodeling at 16 to 17 weeks and subsequently cardiac hypertrophy at 24 to 26 weeks. Meanwhile, blood pressure and cardiac parameters remained normal at 8 to 10 weeks. Additional ablation of TP (TxA<sub>2</sub> receptor) not only restrained EDC and the downregulation of NO signaling in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice but also ameliorated the cardiovascular abnormalities. Stimulation of <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> vessels with acetylcholine in the presence of platelets led to increased TxA<sub>2</sub> generation. COX-1 disruption in bone marrow-derived cells failed to affect the development of high blood pressure and vascular remodeling in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice though it largely suppressed the increase of plasma TxB<sub>2</sub> (TxA<sub>2</sub> metabolite) level.</p><p><strong>Conclusions: </strong>Our study demonstrates that the non-TxA<sub>2</sub> prostanoids/T
背景:由内皮 COX(环氧化酶)合成的前列腺素 I2 在某些血管中可引起有效的血管舒张,但在另一些血管中却会引起内皮依赖性收缩(EDC),这一点令人费解。前列腺素 I2 的产生和 EDC 在高血压等疾病中可能会增强。然而,PGIS(前列腺素 I2 合成酶)的缺乏如何影响 EDC,以及这与随之而来的心血管病变有何关联,这些问题在很大程度上仍是未知数:用野生型、Pgis 基因敲除(Pgis-/-)和 Pgis/thromboxane 类前列腺素受体基因(Tp)双敲除(Pgis-/-Tp-/-)小鼠、移植了未分化的野生型或 Cox-1-/- 骨髓细胞的 Pgis-/- 小鼠以及人类脐动脉进行了实验。通过高效液相色谱-质谱法测量了 COX 衍生的前列腺素。通过等长力测量评估了不同类型动脉的血管运动反应。监测了不同年龄小鼠的高血压、血管重塑和心脏肥大参数:结果:Pgis-/-或 PGIS 抑制的动脉在乙酰胆碱作用下产生 PGF2α、PGE2 和微量 PGD2,但不产生血栓素 A2 (TxA2)。PGIS 缺乏会导致体内外 EDC 的恶化或发生。在 Pgis-/- 主动脉中,内皮依赖性超极化没有改变,但 eNOS(内皮一氧化氮合酶)在 Ser1177 和 Thr495 的磷酸化水平发生了改变,NO 的产生和乙酰胆碱诱发的 NO 依赖性松弛明显减少。Pgis-/- 小鼠在 16 至 17 周时出现高血压和血管重塑,随后在 24 至 26 周时出现心脏肥大。与此同时,血压和心脏参数在 8 至 10 周时保持正常。额外的 TP(TxA2 受体)消融不仅抑制了 Pgis-/- 小鼠的 EDC 和 NO 信号的下调,还改善了心血管异常。在血小板存在的情况下,用乙酰胆碱刺激 Pgis-/- 血管会导致 TxA2 生成增加。骨髓衍生细胞中的 COX-1 干扰虽然在很大程度上抑制了血浆 TxB2(TxA2 代谢物)水平的升高,但未能影响 Pgis-/- 小鼠高血压的发展和血管重塑:我们的研究表明,当 PGIS 缺乏时,非 TxA2 前列腺素/TP 轴在介导 EDC 和心血管疾病的增加中发挥着重要作用,这表明 TP 是 PGIS 缺乏相关疾病的一个有前景的治疗靶点。
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引用次数: 0
A New Piece to the AMPK Puzzle in Heart Repair: Phosphorylation of β-Arrestin-1. AMPK 在心脏修复中的新作用:β-阿restin-1的磷酸化。
IF 19.3 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-30 Epub Date: 2024-08-29 DOI: 10.1161/CIRCRESAHA.124.325195
Julio Silva-Neto, Walter J Koch
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引用次数: 0
Single-Cell Sleuthing: Cracking the Monocyte Code for Cardiovascular Clues. 单细胞侦探:破解单核细胞密码,寻找心血管线索
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-30 Epub Date: 2024-08-29 DOI: 10.1161/CIRCRESAHA.124.325134
Catherine C Hedrick
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引用次数: 0
Meet the First Authors. 认识第一作者
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-30 Epub Date: 2024-08-29 DOI: 10.1161/RES.0000000000000690
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引用次数: 0
Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study. 青年 2 型糖尿病患者的内皮功能障碍:临床转化研究
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS 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

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.

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。
{"title":"Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study.","authors":"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","doi":"10.1161/CIRCRESAHA.124.324272","DOIUrl":"10.1161/CIRCRESAHA.124.324272","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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; <i>P</i>=0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; <i>P</i><0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; <i>P</i>=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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"639-650"},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11361354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Biomimetic Nanodisks Are Effective Against Tubulointerstitial Fibrosis via Targeting Interstitial Microenvironment. 仿生纳米盘通过靶向间质微环境有效防治输卵管间质纤维化
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-30 Epub Date: 2024-08-02 DOI: 10.1161/CIRCRESAHA.124.324322
Chuchu Zhou, Rou Tang, Huajin Tan, Yige Yang, Peipei Meng, He Li, Kaichao Song, Xiaochuan Tan, Xiuping Guo, Ling Ren, Shuwang He, Ya Meng, Yumei Hao, Mingbao Lin, Yujia Zhang, Hongdong Huang, Lulu Wang, Wensheng Zheng
{"title":"Biomimetic Nanodisks Are Effective Against Tubulointerstitial Fibrosis via Targeting Interstitial Microenvironment.","authors":"Chuchu Zhou, Rou Tang, Huajin Tan, Yige Yang, Peipei Meng, He Li, Kaichao Song, Xiaochuan Tan, Xiuping Guo, Ling Ren, Shuwang He, Ya Meng, Yumei Hao, Mingbao Lin, Yujia Zhang, Hongdong Huang, Lulu Wang, Wensheng Zheng","doi":"10.1161/CIRCRESAHA.124.324322","DOIUrl":"10.1161/CIRCRESAHA.124.324322","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e150-e153"},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Biological and Procedural Predictors of Outcome in the Stroke Preclinical Assessment Network (SPAN) Trial. 中风临床前评估网络 (SPAN) 试验结果的生物学和程序预测因素。
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-16 Epub Date: 2024-07-22 DOI: 10.1161/CIRCRESAHA.123.324139
Andreia Morais, Takahiko Imai, Xuyan Jin, Joseph J Locascio, Ligia Boisserand, Alison L Herman, Anjali Chauhan, Jessica Lamb, Karisma Nagarkatti, Marcio A Diniz, Mariia Kumskova, Nirav Dhanesha, Pradip K Kamat, Mohammad Badruzzaman Khan, Krishnan M Dhandapani, Rakesh B Patel, Brijesh Sutariya, Yanrong Shi, Klaus van Leyen, W Taylor Kimberly, David C Hess, Jaroslaw Aronowski, Enrique C Leira, Raymond C Koehler, Anil K Chauhan, Lauren H Sansing, Patrick D Lyden, Cenk Ayata
<p><strong>Background: </strong>The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo.</p><p><strong>Methods: </strong>The study cohort included all mice enrolled and randomized in the SPAN trial (N=1789). Mice were subjected to 60-minute MCAo and followed for a month. Thirteen biological and procedural independent variables and 4 functional (weight loss and 4-point neuroscore on days 1 and 2, corner test on days 7 and 28, and mortality) and 3 tissue (day 2, magnetic resonance imaging infarct volumes and swelling; day 30, magnetic resonance imaging tissue loss) outcome variables were prospectively captured. Multivariable regression with stepwise elimination was used to identify the predictors and their effect sizes.</p><p><strong>Results: </strong>Older age, active circadian stage at MCAo, and thinner and longer filament silicone tips predicted higher mortality. Older age, larger body weight, longer anesthesia duration, and longer filament tips predicted worse neuroscores, while high-fat diet and blood flow monitoring predicted milder neuroscores. Older age and a high-fat diet predicted worse corner test performance. While shorter filament tips predicted more ipsiversive turning, longer filament tips appeared to predict contraversive turning. Age, sex, and weight interacted when predicting the infarct volume. Older age was associated with smaller infarcts on day 2 magnetic resonance imaging, especially in animals with larger body weights; this association was most conspicuous in females. High-fat diet also predicted smaller infarcts. In contrast, the use of cerebral blood flow monitoring and more severe cerebral blood flow drop during MCAo, longer anesthesia, and longer filament tips all predicted larger infarcts. Bivariate analyses among the dependent variables highlighted a disconnect between tissue and functional outcomes.</p><p><strong>Conclusions: </strong>Our analyses identified variables affecting endovascular filament MCAo outcome, an experimental stroke model used worldwide. Multiple regression refuted some commonly reported predictors and revealed previously unrecognized associations. Given the multicenter prospective design that represents a sampling of real-world conditions, the degree of heterogeneity mimicking clinical trials, the large number of predictors adjusted for in the multivaria
背景:SPAN试验(脑卒中临床前评估网络)是在实验性局灶性脑缺血中使用血管内丝状大脑中动脉闭塞(MCAo)测试急性脑卒中干预措施的最大规模临床前研究。除了针对对照组测试干预措施外,前瞻性设计还捕捉了大量生物和程序变量,凸显了多中心结构带来的可能影响卒中预后的巨大异质性。在此,我们利用 SPAN 试验前所未有的样本量和前瞻性设计来确定影响瞬时血管内丝 MCAo 实验性卒中结果的生物和程序变量:研究队列包括所有参加 SPAN 试验并随机分配的小鼠(N=1789)。对小鼠进行 60 分钟的 MCAo,并随访一个月。前瞻性地采集了13个生物和程序自变量、4个功能变量(第1天和第2天的体重减轻和4点神经评分、第7天和第28天的转角测试以及死亡率)和3个组织变量(第2天,磁共振成像梗死体积和肿胀;第30天,磁共振成像组织损失)。采用逐步剔除法进行多变量回归,以确定预测因素及其效应大小:年龄越大、MCAo 的昼夜节律阶段越活跃、硅胶尖端越细越长,预示死亡率越高。年龄越大、体重越重、麻醉时间越长、硅胶头丝越长,预示神经系统评分越差,而高脂饮食和血流监测预示神经系统评分越轻。年龄较大和高脂肪饮食预示着转角测试成绩较差。较短的丝尖预示着更多的同向转弯,而较长的丝尖似乎预示着反向转弯。年龄、性别和体重在预测梗死体积时相互影响。年龄越大,第2天磁共振成像显示的梗死面积越小,尤其是体重较大的动物;这种关联在雌性动物中最为明显。高脂肪饮食也会导致脑梗塞体积变小。相反,使用脑血流监测、MCAo期间脑血流下降更严重、麻醉时间更长以及丝尖更长都预示着梗死面积更大。因变量之间的双变量分析凸显了组织和功能结果之间的脱节:我们的分析确定了影响血管内丝 MCAo 结果的变量,这是一种全球通用的实验性中风模型。多元回归驳斥了一些常见的预测因素,并揭示了以前未曾认识到的关联。鉴于多中心前瞻性设计代表了真实世界的抽样情况,异质性程度模拟了临床试验,在多变量模型中调整了大量预测因素,以及样本量大,我们认为这是迄今为止对临床前卒中结局预测因素最权威的分析。未来的多中心脑卒中实验应标准化或至少确保均衡代表本文确定的潜在混杂因素的生物和程序变量。
{"title":"Biological and Procedural Predictors of Outcome in the Stroke Preclinical Assessment Network (SPAN) Trial.","authors":"Andreia Morais, Takahiko Imai, Xuyan Jin, Joseph J Locascio, Ligia Boisserand, Alison L Herman, Anjali Chauhan, Jessica Lamb, Karisma Nagarkatti, Marcio A Diniz, Mariia Kumskova, Nirav Dhanesha, Pradip K Kamat, Mohammad Badruzzaman Khan, Krishnan M Dhandapani, Rakesh B Patel, Brijesh Sutariya, Yanrong Shi, Klaus van Leyen, W Taylor Kimberly, David C Hess, Jaroslaw Aronowski, Enrique C Leira, Raymond C Koehler, Anil K Chauhan, Lauren H Sansing, Patrick D Lyden, Cenk Ayata","doi":"10.1161/CIRCRESAHA.123.324139","DOIUrl":"10.1161/CIRCRESAHA.123.324139","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The study cohort included all mice enrolled and randomized in the SPAN trial (N=1789). Mice were subjected to 60-minute MCAo and followed for a month. Thirteen biological and procedural independent variables and 4 functional (weight loss and 4-point neuroscore on days 1 and 2, corner test on days 7 and 28, and mortality) and 3 tissue (day 2, magnetic resonance imaging infarct volumes and swelling; day 30, magnetic resonance imaging tissue loss) outcome variables were prospectively captured. Multivariable regression with stepwise elimination was used to identify the predictors and their effect sizes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Older age, active circadian stage at MCAo, and thinner and longer filament silicone tips predicted higher mortality. Older age, larger body weight, longer anesthesia duration, and longer filament tips predicted worse neuroscores, while high-fat diet and blood flow monitoring predicted milder neuroscores. Older age and a high-fat diet predicted worse corner test performance. While shorter filament tips predicted more ipsiversive turning, longer filament tips appeared to predict contraversive turning. Age, sex, and weight interacted when predicting the infarct volume. Older age was associated with smaller infarcts on day 2 magnetic resonance imaging, especially in animals with larger body weights; this association was most conspicuous in females. High-fat diet also predicted smaller infarcts. In contrast, the use of cerebral blood flow monitoring and more severe cerebral blood flow drop during MCAo, longer anesthesia, and longer filament tips all predicted larger infarcts. Bivariate analyses among the dependent variables highlighted a disconnect between tissue and functional outcomes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our analyses identified variables affecting endovascular filament MCAo outcome, an experimental stroke model used worldwide. Multiple regression refuted some commonly reported predictors and revealed previously unrecognized associations. Given the multicenter prospective design that represents a sampling of real-world conditions, the degree of heterogeneity mimicking clinical trials, the large number of predictors adjusted for in the multivaria","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"575-592"},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11428171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting HFpEF: Unlocking the Potential of Glucagon Receptor Blockade. 靶向高频低血钾症:释放胰高血糖素受体阻滞剂的潜力。
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-16 Epub Date: 2024-08-15 DOI: 10.1161/CIRCRESAHA.124.325130
Leandro Santiago Padilla, Gabriele G Schiattarella
{"title":"Targeting HFpEF: Unlocking the Potential of Glucagon Receptor Blockade.","authors":"Leandro Santiago Padilla, Gabriele G Schiattarella","doi":"10.1161/CIRCRESAHA.124.325130","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325130","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 5","pages":"629-631"},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multimodal Imaging-Assisted Intravascular Theranostic Photoactivation on Atherosclerotic Plaque. 动脉粥样硬化斑块上的多模态成像辅助血管内 Theranostic 光激活。
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-16 Epub Date: 2024-07-11 DOI: 10.1161/CIRCRESAHA.123.323970
Jin Hyuk Kim, Joon Woo Song, Yeon Hoon Kim, Hyun Jung Kim, Ryeong Hyun Kim, Ye Hee Park, Hyeong Soo Nam, Dong Oh Kang, Hongki Yoo, Kyeongsoon Park, Jin Won Kim

Background: Atherosclerosis is a chronic inflammatory disease causing a fatal plaque rupture, and its key aspect is a failure to resolve inflammation. We hypothesize that macrophage-targeted near-infrared fluorescence emitting photoactivation could simultaneously assess macrophage/lipid-rich plaques in vivo and facilitate inflammation resolution.

Methods: We fabricated a Dectin-1-targeted photoactivatable theranostic agent through the chemical conjugation of the near-infrared fluorescence-emitting photosensitizer chlorin e6 and the Dectin-1 ligand laminarin (laminarin-chlorin e6 [LAM-Ce6]). Intravascular photoactivation by a customized fiber-based diffuser after administration of LAM-Ce6 effectively reduced inflammation in the targeted plaques of atherosclerotic rabbits in vivo as serially assessed by dual-modal optical coherence tomography-near-infrared fluorescence structural-molecular catheter imaging after 4 weeks.

Results: The number of apoptotic macrophages peaked at 1 day after laser irradiation and then resolved until 4 weeks. Autophagy was strongly augmented 1 hour after the light therapy, with the formation of autophagolysosomes. LAM-Ce6 photoactivation increased the terminal deoxynucleotidyl transferase dUTP (deoxyuridine triphosphate) nick end labeling/RAM11 (rabbit monocyte/macrophage antibody)- and MerTK (c-Mer tyrosine kinase)-positive cells in the plaques, suggesting enhanced efferocytosis. In line with inflammation resolution, photoactivation reduced the plaque burden through fibrotic replacement via the TGF (transforming growth factor)-β/CTGF (connective tissue growth factor) pathway.

Conclusions: Optical coherence tomography-near-infrared fluorescence imaging-guided macrophage Dectin-1-targetable photoactivation could induce the transition of macrophage/lipid-rich plaques into collagen-rich lesions through autophagy-mediated inflammation resolution and TGF-β-dependent fibrotic replacement. This novel strategy offers a new opportunity for the catheter-based theranostic strategy.

背景:动脉粥样硬化是一种慢性炎症性疾病,会导致致命的斑块破裂,其关键在于炎症无法消除。我们假设,巨噬细胞靶向近红外荧光发射光激活剂可同时评估体内巨噬细胞/脂质丰富的斑块,并促进炎症的解决:我们通过化学共轭近红外荧光发射光敏剂氯素e6和Dectin-1配体层粘蛋白-氯素e6,制备了一种Dectin-1靶向可光激活治疗剂。4 周后,通过双模态光学相干断层扫描-近红外荧光结构-分子导管成像进行序列评估,服用层光素-氯素 e6 后,通过定制的纤维扩散器进行血管内光激活,可有效减少体内动脉粥样硬化兔子靶斑块中的炎症。凋亡巨噬细胞的数量在激光照射后 1 天达到峰值,然后在 4 周前消退。光疗后 1 小时,巨噬细胞自噬现象强烈增加,并形成自噬溶酶体。层析氯化霉素 e6 光激活增加了斑块中末端脱氧核苷酸转移酶 dUTP 缺口标记/RAM11-和 MerTK(c-Mer 酪氨酸激酶)-阳性细胞的数量,这表明流出细胞增多。随着炎症的消退,光激活通过TGF(转化生长因子)-β/CTGF(结缔组织生长因子)途径进行纤维化替代,从而减轻了斑块的负担:光学相干断层扫描-近红外荧光成像引导的巨噬细胞Dectin-1靶向光激活可通过自噬介导的炎症消退和TGF-β依赖的纤维化替代,诱导富含巨噬细胞/脂质的斑块转变为富含胶原蛋白的病变。这种新策略为基于导管的治疗策略提供了新的机遇。
{"title":"Multimodal Imaging-Assisted Intravascular Theranostic Photoactivation on Atherosclerotic Plaque.","authors":"Jin Hyuk Kim, Joon Woo Song, Yeon Hoon Kim, Hyun Jung Kim, Ryeong Hyun Kim, Ye Hee Park, Hyeong Soo Nam, Dong Oh Kang, Hongki Yoo, Kyeongsoon Park, Jin Won Kim","doi":"10.1161/CIRCRESAHA.123.323970","DOIUrl":"10.1161/CIRCRESAHA.123.323970","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis is a chronic inflammatory disease causing a fatal plaque rupture, and its key aspect is a failure to resolve inflammation. We hypothesize that macrophage-targeted near-infrared fluorescence emitting photoactivation could simultaneously assess macrophage/lipid-rich plaques in vivo and facilitate inflammation resolution.</p><p><strong>Methods: </strong>We fabricated a Dectin-1-targeted photoactivatable theranostic agent through the chemical conjugation of the near-infrared fluorescence-emitting photosensitizer chlorin e6 and the Dectin-1 ligand laminarin (laminarin-chlorin e6 [LAM-Ce6]). Intravascular photoactivation by a customized fiber-based diffuser after administration of LAM-Ce6 effectively reduced inflammation in the targeted plaques of atherosclerotic rabbits in vivo as serially assessed by dual-modal optical coherence tomography-near-infrared fluorescence structural-molecular catheter imaging after 4 weeks.</p><p><strong>Results: </strong>The number of apoptotic macrophages peaked at 1 day after laser irradiation and then resolved until 4 weeks. Autophagy was strongly augmented 1 hour after the light therapy, with the formation of autophagolysosomes. LAM-Ce6 photoactivation increased the terminal deoxynucleotidyl transferase dUTP (deoxyuridine triphosphate) nick end labeling/RAM11 (rabbit monocyte/macrophage antibody)- and MerTK (c-Mer tyrosine kinase)-positive cells in the plaques, suggesting enhanced efferocytosis. In line with inflammation resolution, photoactivation reduced the plaque burden through fibrotic replacement via the TGF (transforming growth factor)-β/CTGF (connective tissue growth factor) pathway.</p><p><strong>Conclusions: </strong>Optical coherence tomography-near-infrared fluorescence imaging-guided macrophage Dectin-1-targetable photoactivation could induce the transition of macrophage/lipid-rich plaques into collagen-rich lesions through autophagy-mediated inflammation resolution and TGF-β-dependent fibrotic replacement. This novel strategy offers a new opportunity for the catheter-based theranostic strategy.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e114-e132"},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Glucagon Receptor Antagonist for Heart Failure With Preserved Ejection Fraction. 胰高血糖素受体拮抗剂治疗射血分数保留型心力衰竭
IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-16 Epub Date: 2024-07-16 DOI: 10.1161/CIRCRESAHA.124.324706
Chen Gao, Zhaojun Xiong, Yunxia Liu, Meng Wang, Menglong Wang, Tian Liu, Jianfang Liu, Shuxun Ren, Nancy Cao, Hai Yan, Daniel J Drucker, Christoph Daniel Rau, Tomohiro Yokota, Jijun Huang, Yibin Wang

Background: Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized.

Method: We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts.

Results: In contrast to the post-transverse aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-transverse aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress.

Conclusions: These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.

背景:射血分数保留型心力衰竭(HFpEF)是一项新出现的尚未满足的重大需求,也是心脏病学临床面临的最重大挑战之一。HFpEF 的发病机制与多种危险因素有关。高血压和与肥胖相关的代谢紊乱是 HFpEF 患者最常见的两种合并症。虽然高血压引起的机械负荷过重早已被认为是导致射血分数降低的心力衰竭的一个重要因素,但机械负荷过重和代谢紊乱在 HFpEF 发病机制中的协同作用仍鲜为人知:方法:我们通过对瘦C57Bl/6J或肥胖/糖尿病B6.Cg-Lepob/J(ob/ob)小鼠进行横向主动脉缩窄,研究了心脏同时承受机械和代谢压力所产生的功能结果及其潜在机制,随后进行了单核RNA-seq分析,并对两个实验队列中受到不同影响的顶级信号通路进行了靶向操作:结果:与经主动脉缩窄后的 C57Bl/6J 瘦小鼠相比,经主动脉缩窄后的 ob/ob 小鼠随着时间的推移出现了射血分数降低的心力衰竭病理特征,射血分数没有明显变化,但却出现了 HFpEF 的特征性病理特征,包括舒张功能障碍、心脏肥大恶化和病理重塑,以及运动不耐受性进一步恶化。单核RNA-seq分析显示,同时受到压力过载和肥胖/糖尿病压力的心肌细胞发生了显著的转录组重排,这与单独受到压力过载或肥胖/糖尿病压力的心肌细胞明显不同。此外,胰高血糖素信号被确定为与高频心衰相关的心肌细胞中受影响最大的信号通路。在两个独立的临床前模型中,用胰高血糖素受体拮抗剂治疗可明显改善高频心衰相关病理特征的发展。重要的是,心肌细胞特异性胰高血糖素受体基因缺失也能显著改善心脏功能对压力过载和代谢压力的反应:这些发现确定了心肌细胞中的胰高血糖素受体信号转导是高频心衰进展的关键决定因素,并为胰高血糖素受体拮抗剂作为该疾病的一种潜在疗法提供了概念验证支持。
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Circulation research
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