Basic Research in Cardiology最新文献_第2页

Coronary microvascular dysfunction is a determinant of perfusion-contraction matching during ischemia. 冠状动脉微血管功能障碍是缺血时血流收缩匹配的决定因素。

IF 9.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Basic Research in Cardiology

Pub Date : 2025-12-11 DOI: 10.1007/s00395-025-01151-8

John M Canty,Brian R Weil

引用次数: 0

Dysfunctional high-density lipoprotein particles are associated with cardiac alterations in cancer patients and tumor-bearing mice receiving doxorubicin. 功能失调的高密度脂蛋白颗粒与接受阿霉素治疗的癌症患者和荷瘤小鼠的心脏改变有关。

IF 9.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Basic Research in Cardiology

Pub Date : 2025-12-01 DOI: 10.1007/s00395-025-01149-2

Carmelita Abrahams,Wanzhu Zhang,Nonhlakanipho Sangweni,Vitaris Kodogo,Nkanyiso Hadebe,Emmy Okello,Rabia Johnson,Nicholas J Woudberg,Karen Sliwa,Sandrine Lecour

Cancer patients receiving doxorubicin (DOX) chemotherapy are at high risk of developing cardiac alterations, but the mechanisms remain elusive. Both breast cancer and DOX therapy are associated with dyslipidemia. We aimed to investigate whether changes in high-density lipoprotein (HDL) particles subclass distribution and functionalities are associated with DOX-induced cardiac alterations in breast cancer patients and tumor-bearing mice. HDL particles subclasses were assessed using the Lipoprint® system in breast cancer patients (n = 34) and tumor-bearing mice at baseline and after receiving DOX chemotherapy. HDL particles antioxidative properties were assessed by measuring paraoxonase-1 (PON1) activity. The ability of isolated HDL particles to protect against DOX-induced cytotoxicity was assessed in H9c2 cells. In breast cancer patients, DOX therapy reduced intermediate HDL particles subclasses, an effect that positively correlated with cardiac alterations. In mice, breast cancer shifted HDL particles subclasses distribution from intermediate to large HDL particles while DOX therapy increased small HDL particles. Both breast cancer and DOX therapy were associated with reduced PON1 activity. The decrease in intermediate HDL particles correlated with poorer cardiac function and lower PON1 activity. Interestingly, HDL particles isolated from tumor-bearing mice or from mice receiving DOX failed to protect H9c2 cells against DOX-induced cytotoxicity compared to HDL particles of healthy mice. In our study, a shift in HDL particles subclasses and functionalities correlated with cardiac alterations in cancer patients and mice treated with DOX. Consequently, our data warrant further research to explore whether targeting HDL particles may represent a therapeutic strategy to limit DOX-induced cardiotoxicity in breast cancer patients.

接受多柔比星（DOX）化疗的癌症患者发生心脏改变的风险很高，但其机制尚不清楚。乳腺癌和DOX治疗都与血脂异常有关。我们的目的是研究高密度脂蛋白（HDL）颗粒亚类分布和功能的变化是否与dox诱导的乳腺癌患者和荷瘤小鼠心脏改变有关。在基线和接受DOX化疗后，使用lipopprint®系统对乳腺癌患者（n = 34）和荷瘤小鼠的HDL颗粒亚类进行评估。通过测定对氧磷酶-1 （PON1）活性来评价HDL颗粒的抗氧化性能。在H9c2细胞中评估了分离的HDL颗粒对dox诱导的细胞毒性的保护能力。在乳腺癌患者中，DOX治疗降低了中间HDL颗粒亚类，这种效果与心脏改变呈正相关。在小鼠中，乳腺癌将HDL颗粒亚类分布从中等转移到大HDL颗粒，而DOX治疗增加了小HDL颗粒。乳腺癌和DOX治疗均与PON1活性降低有关。中间HDL颗粒的减少与心功能变差和PON1活性降低相关。有趣的是，与健康小鼠的HDL颗粒相比，从荷瘤小鼠或接受DOX的小鼠中分离的HDL颗粒不能保护H9c2细胞免受DOX诱导的细胞毒性。在我们的研究中，在接受DOX治疗的癌症患者和小鼠中，HDL颗粒亚类和功能的改变与心脏改变相关。因此，我们的数据值得进一步研究，以探索靶向HDL颗粒是否可能代表一种限制dox诱导的乳腺癌患者心脏毒性的治疗策略。

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引用次数: 0

Mixed lineage kinase 3 contributes to myocardial ischemia/reperfusion injury by regulating neutrophil activation. 混合谱系激酶3通过调节中性粒细胞活化参与心肌缺血/再灌注损伤。

IF 8 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Basic Research in Cardiology

Pub Date : 2025-12-01 Epub Date: 2025-11-11 DOI: 10.1007/s00395-025-01145-6

Zilong Xiao, Xiang Wei, Zhonglei Xie, Qingxing Chen, Ruizhen Chen, Ziqing Yu, Yixiu Liang, Yangang Su, Junbo Ge

Mixed lineage kinase 3 (MLK3), a member of the MAP3K family, is known to participate in cellular stress and inflammatory responses, but its role in neutrophil-mediated myocardial ischemia-reperfusion (I/R) injury remains unclear. In this study, we investigated the function and downstream signaling of MLK3 in neutrophils using genetically modified mouse models with neutrophil-specific MLK3 knockout or overexpression. MLK3 deficiency in neutrophils reduced infarct size, improved cardiac function, and decreased neutrophil infiltration, NET formation, and pro-inflammatory cytokine release following I/R. Transcriptomic profiling revealed that MLK3 promotes the expression of the antimicrobial peptide CRAMP by stabilizing and activating the transcription factor C/EBPβ. Administration of exogenous CRAMP abolished the protective effects of MLK3 deletion, confirming its functional relevance. Furthermore, treatment with CEP-1347, a small-molecule MLK3 inhibitor, attenuated myocardial injury, reduced apoptosis, and limited adverse remodeling in vivo. In acute myocardial infarction (AMI) patients, elevated levels of phosphorylated MLK3 (pMLK3) in circulating neutrophils were associated with increased levels of MPO-DNA, cTnT, and CK-MB, as well as a trend toward higher rates of cardiovascular rehospitalization. These findings identify a neutrophil-intrinsic MLK3-C/EBPβ-CRAMP axis that amplifies myocardial inflammation and injury, and suggest MLK3 as a promising therapeutic target and potential biomarker for ischemic heart disease.

混合谱系激酶3 （MLK3）是MAP3K家族的一员，已知参与细胞应激和炎症反应，但其在中性粒细胞介导的心肌缺血再灌注（I/R）损伤中的作用尚不清楚。在这项研究中，我们通过中性粒细胞特异性MLK3敲除或过表达的转基因小鼠模型研究了MLK3在中性粒细胞中的功能和下游信号传导。中性粒细胞MLK3缺乏减少梗死面积，改善心功能，减少I/R后中性粒细胞浸润、NET形成和促炎细胞因子释放。转录组学分析显示，MLK3通过稳定和激活转录因子C/EBPβ来促进抗菌肽CRAMP的表达。外源性camp消除了MLK3缺失的保护作用，证实了其功能相关性。此外，CEP-1347（一种小分子MLK3抑制剂）治疗可减轻心肌损伤，减少细胞凋亡，并限制体内不良重构。在急性心肌梗死（AMI）患者中，循环中性粒细胞中磷酸化MLK3 （pMLK3）水平升高与MPO-DNA、cTnT和CK-MB水平升高相关，并有心血管再住院率升高的趋势。这些发现确定了中性粒细胞内生性MLK3- c /EBPβ-CRAMP轴可放大心肌炎症和损伤，并提示MLK3是一种有希望的治疗靶点和缺血性心脏病的潜在生物标志物。

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引用次数: 0

Correction: IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT): a small animal acute myocardial infarction randomized-controlled multicenter study on the effect of ischemic preconditioning. 修正：改善心脏保护疗法的临床前评估（IMPACT）：一项小动物急性心肌梗死缺血性预处理效果的随机对照多中心研究。

IF 8 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Basic Research in Cardiology

Pub Date : 2025-12-01 DOI: 10.1007/s00395-025-01142-9

Sauri Hernandez-Resendiz, Reinis Vilskersts, David Aluja, Ioanna Andreadou, Péter Bencsik, Maija Dambrova, Panagiotis Efentakis, Fei Gao, Zoltán Giricz, Gábor B Brenner, Nabil V Sayour, Tamás G Gergely, András Makkos, Javier Inserte, Roisin Kelly-Laubscher, Attila Kiss, Thomas Krieg, Brenda R Kwak, Sandrine Lecour, Gary Lopaschuk, Michał Mączewski, Michał Waszkiewicz, Marta Oknińska, Pasquale Pagliaro, Bruno Podesser, Hiran A Prag, Marisol Ruiz-Meana, Tamara Szabados, Coert J Zuurbier, Péter Ferdinandy, Derek J Hausenloy

引用次数: 0

Serum amyloid A in HFpEF and cardiometabolic diseases. HFpEF与心脏代谢疾病的血清淀粉样蛋白A。

IF 9.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Basic Research in Cardiology

Pub Date : 2025-11-28 DOI: 10.1007/s00395-025-01150-9

Luo Liu,Rongling Wang,Stefano Strocchi,Tolga Eroglu,Natasha Nambiar,Sarah V Liévano Contreras,Saskia A Diezel,Gabriele G Schiattarella

Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of all heart failure cases, and its prevalence is projected to rise further. Among its heterogeneous subtypes, cardiometabolic HFpEF, which is driven by metabolic dysfunction, represents a globally predominant form. Recent advances in preclinical models have highlighted metabolic disturbances and systemic inflammation as key contributors to HFpEF pathogenesis. While much attention has focused on classical inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), the full spectrum of upstream inflammatory drivers and the therapeutic strategies targeting inflammation in cardiometabolic HFpEF remain incompletely defined. Among emerging candidates, serum amyloid A (SAA) family proteins, highly inducible acute-phase proteins, have attracted growing attention due to their elevated levels in chronic metabolic diseases. Here, we summarize clinical associations between elevated SAA levels and major cardiometabolic conditions-including obesity, diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), and hypertension-and discuss potential mechanisms based on preclinical studies. We place particular emphasis on the known and potential pathogenetic role of SAA in cardiometabolic HFpEF, where it may contribute to systemic inflammation, endothelial dysfunction, and myocardial fibrosis. Overall, this review aims to advance understanding of SAA in HFpEF and cardiometabolic disease, and to support translational efforts toward improved diagnosis and treatment.

保留射血分数的心力衰竭（HFpEF）占所有心力衰竭病例的一半以上，其患病率预计将进一步上升。在其异质性亚型中，由代谢功能障碍驱动的心脏代谢性HFpEF代表了全球主要形式。临床前模型的最新进展表明，代谢紊乱和全身性炎症是HFpEF发病机制的关键因素。虽然经典炎症介质如白细胞介素-6 （IL-6）和肿瘤坏死因子-α (TNF-α)备受关注，但上游炎症驱动因子的全谱和针对心脏代谢性HFpEF炎症的治疗策略仍未完全确定。在新出现的候选药物中，血清淀粉样蛋白A （SAA）家族蛋白是高度诱导的急性期蛋白，由于其在慢性代谢性疾病中的水平升高而引起越来越多的关注。在这里，我们总结了SAA水平升高与主要心脏代谢疾病（包括肥胖、糖尿病、代谢功能障碍相关的脂肪变性肝病（MASLD，以前的NAFLD）和高血压）之间的临床关联，并基于临床前研究讨论了潜在的机制。我们特别强调SAA在心脏代谢性HFpEF中已知的和潜在的致病作用，它可能导致全身炎症、内皮功能障碍和心肌纤维化。总之，本综述旨在增进对SAA在HFpEF和心脏代谢疾病中的理解，并支持改进诊断和治疗的转化工作。

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引用次数: 0

Mechanical unloading coupled with coronary reperfusion stimulates cardiomyocyte proliferation and prevents unloading-induced fibrosis after myocardial infarction. 机械卸荷结合冠脉再灌注刺激心肌细胞增殖，防止心肌梗死后卸荷引起的纤维化。

IF 9.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Basic Research in Cardiology

Pub Date : 2025-11-22 DOI: 10.1007/s00395-025-01147-4

Sean O Bello,Charanjit Singh,Filippo Perbellini,Prakash P Punjabi,Cesare M Terracciano

Percutaneous left ventricular assist devices (LVADs) have become essential tools during coronary reperfusion in high-risk PCI. Significant reduction in infarct propagation is observed when mechanical unloading is coupled with reperfusion, but little is known of the effect this reduction in wall stress and extracellular matrix with LVADs has on the heart's regenerative capacity. This study investigates the effect coronary reperfusion coupled with mechanical unloading has on myocardial fibrosis, and the impact of these changes in extracellular matrix on the heart's regenerative potential. MI was induced by coronary artery ligation in Lewis rats. Hearts underwent permanent coronary ligation (AMI) or were reperfused after 90 min (AMI/R). In each group, hearts were either loaded (AMI-L or AMI/R-L) or unloaded (AMI-U or AMI/R-U). In the unloaded subgroup, the infarcted hearts were explanted after 90 min and transplanted into the abdomen of healthy recipients via heterotopic abdominal heart-lung transplantation. The recipient's heart acted as control. Hearts were analysed on day 7. 30 hearts were studied. In the permanent ligation group, fibrosis increased in both the loaded and unloaded hearts with no significant rise in cardiomyocyte proliferation. After coronary reperfusion, no increase in fibrosis was observed with mechanical unloading but cardiomyocyte proliferation rose significantly (AMI/R-L vs AMI/R-U p = 0.0001). Cardiomyocyte proliferative rate in the loaded and unloaded hearts was 0.6% and 3.7%, respectively, after permanent ligation, and 0.5% and 10.4%, respectively, after coronary reperfusion. These data show that coronary reperfusion coupled with mechanical unloading reduces myocardial fibrosis and upregulates cardiomyocyte proliferation after myocardial infarction.

经皮左心室辅助装置（lvad）已成为高危PCI患者冠状动脉再灌注的重要工具。当机械卸载与再灌注相结合时，可以观察到梗死扩展的显著减少，但对于lvad的壁应力和细胞外基质的减少对心脏再生能力的影响知之甚少。本研究探讨冠状动脉再灌注联合机械卸载对心肌纤维化的影响，以及细胞外基质的这些变化对心脏再生潜能的影响。Lewis大鼠冠状动脉结扎诱导心肌梗死。心脏接受永久性冠状动脉结扎（AMI）或90分钟后再灌注（AMI/R）。在每一组中，心脏要么有负荷（AMI- l或AMI/R-L），要么没有负荷（AMI- u或AMI/R-U）。在无负荷亚组，梗死心脏在90分钟后被移植，通过异位腹部心肺移植移植到健康受者的腹部。接受者的心脏作为对照。第7天进行心脏分析。研究了30颗心脏。在永久性结扎组，心肌细胞增殖无明显增加，但心肌纤维化在负荷和未负荷心脏均有所增加。冠状动脉再灌注后，机械卸载未观察到纤维化增加，但心肌细胞增殖明显增加（AMI/R-L vs AMI/R-U p = 0.0001）。冠脉再灌注后，心肌细胞增殖率分别为0.5%和10.4%。永久性结扎后，心肌细胞增殖率为0.6%和3.7%。这些数据表明，冠脉再灌注联合机械卸载可减少心肌纤维化，上调心肌梗死后心肌细胞增殖。

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引用次数: 0

Impairment of local metabolic coronary control involves perfusion-contraction matching not supply-demand imbalance. 局部代谢性冠状动脉控制损害涉及灌注收缩匹配而非供需失衡。

IF 9.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Basic Research in Cardiology

Pub Date : 2025-11-20 DOI: 10.1007/s00395-025-01148-3

Salman I Essajee,Gregory M Dick,Selina M Tucker,Cooper M Warne,C Alberto Figueroa,Daniel A Beard,Dirk J Duncker,Johnathan D Tune

Understanding of local metabolic control of coronary flow remains stifled by debate around data interpretation and anticipated outcomes. To address this question we performed experiments in a cannulated coronary preparation in swine to precisely control flow as myocardial oxygen consumption (MVO2) and contractile function were modulated by dobutamine (1-10 μg/kg/min, iv), reductions in coronary perfusion pressure (CPP), and the inhibition of voltage-gated K+ channels with 4-aminopyridine (4-AP; 1 mM, ic). Reduction of CPP to 40 mmHg diminished coronary flow (~ 55%; P < 0.001) and systolic wall thickening (~ 35%; P < 0.001). 4-AP-mediated reductions in coronary flow (~ 35%; P = 0.01) and wall thickening (~ 40%; P < 0.05) were restored by returning coronary flow to normal baseline levels. Dobutamine increased heart rate and coronary flow ~ 65% (P < 0.001) and coronary flow remained tightly coupled with MVO2. Inhibition of coronary responses to dobutamine was associated with an ~ 35% reduction in wall thickening and an ~ 50% increase in MVO2. Reductions in CPP, administration of 4-AP, and diminished flow during dobutamine infusion were associated with proportional decreases in coronary flow and MVO2. Wall thickening progressively decreased as coronary flow was reduced below ~ 5.0-7.5 μL/g/beat regardless of whether the decrease was due to diminished "supply" (CPP, 4-AP) or limitations during increased "demand" (flow clamp or restriction with dobutamine). These findings demonstrate that impairments in local metabolic control of coronary flow are reliably demonstrated by decreases in contractile function as a consequence of reductions in the volume of myocardial perfusion per beat.

对冠状动脉血流的局部代谢控制的理解仍然受到数据解释和预期结果的争论的抑制。为了解决这个问题，我们在猪冠状动脉插管制剂中进行了实验，通过多巴酚丁胺（1-10 μg/kg/min, iv）、降低冠状动脉灌注压（CPP）和4-氨基吡啶（4-AP; 1 mM, ic）抑制电压门控K+通道来精确控制心肌耗氧量（MVO2）和收缩功能。CPP降至40 mmHg可减少冠状动脉血流（~ 55%;P < 0.001）和收缩壁增厚（~ 35%;P < 0.001）。通过将冠状动脉血流恢复到正常基线水平，4- ap介导的冠状动脉血流减少（~ 35%,P = 0.01）和壁增厚（~ 40%,P < 0.05）得到恢复。多巴酚丁胺使心率和冠状动脉血流增加65% (P < 0.001)，冠状动脉血流与MVO2保持紧密耦合。抑制冠状动脉对多巴酚丁胺的反应与壁增厚减少35%和MVO2增加50%有关。在多巴酚丁胺输注期间，CPP的降低、4-AP的管理和血流的减少与冠状动脉血流和MVO2成比例的降低有关。当冠状动脉血流低于~ 5.0-7.5 μL/g/次时，壁增厚逐渐减少，无论这种减少是由于“供应”减少（CPP, 4-AP）还是由于“需求”增加时的限制（流量钳或多巴酚丁胺限制）。这些发现表明，心肌每跳动灌注量的减少导致收缩功能的下降，可以可靠地证明冠状动脉血流局部代谢控制的损伤。

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引用次数: 0

Autophagy modulates the mechanism of flow-mediated dilation upstream of telomerase. 自噬调节端粒酶上游血流介导的扩张机制。

IF 9.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Basic Research in Cardiology

Pub Date : 2025-11-14 DOI: 10.1007/s00395-025-01146-5

William E Hughes,Shelby N Hader,Kate Astbury,Lukas Brandt,Karima Ait-Aissa,David D Gutterman,Andreas M Beyer

The non-canonical functions of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase play a critical role in maintaining microvascular homeostasis utilizing both human and rodent models. Previously, we have demonstrated that intact autophagic flux is necessary for the beneficial effects of TERT to maintain microvascular function and redox status in human resistance arterioles. The purpose of this investigation was to examine (1) whether loss of TERT function in vivo resulted in reductions in autophagy/mitophagy and concomitant changes in the mediator of microvascular FMD; (2) whether restoration of autophagy can reverse this pathological switch in dilator mechanism, reduce shear-induced mitochondrial H2O2 production while enhancing NO production. TERT mutant rats were generated and compared to their WT counterparts. Rats were given an autophagy activator (2% trehalose) for 28-days. Isolated mesenteric arteries were used for videomicroscopy, and aortic tissue was collected for immunoblotting. FMD and autophagic flux were measured in arteries in all groups. Loss of TERT function resulted in a switch from NOS-dependent to H2O2-dependent FMD, repressed microvascular shear-induced autophagic flux and NO production, and increased mitochondrial H2O2 production. Activation of autophagy restored NO-mediated dilation in TERT mutant rats, and enhanced shear-induced autophagic flux. We provide evidence that autophagy is necessary for the beneficial role of TERT within maintaining microvascular function, positioning this pathway as a modifiable target to maintain microvascular health by rescuing the endothelial dysfunction caused by loss of TERT signaling.

端粒酶的催化亚基——端粒酶逆转录酶（TERT）的非规范功能在维持人类和啮齿动物微血管稳态中发挥关键作用。之前，我们已经证明，完整的自噬通量是TERT维持微血管功能和人类抵抗小动脉氧化还原状态的有益作用所必需的。本研究的目的是检验(1)体内TERT功能的丧失是否会导致自噬/有丝自噬的减少以及伴随的微血管FMD介质的变化；(2)自噬的恢复是否能够逆转这种扩张机制的病理开关，减少剪切诱导的线粒体H2O2的产生，同时增加NO的产生。生成TERT突变大鼠，并将其与WT对应物进行比较。大鼠给予自噬激活剂（2%海藻糖）28天。分离的肠系膜动脉进行视频显微镜观察，并收集主动脉组织进行免疫印迹。测定各组动脉FMD和自噬通量。TERT功能的缺失导致从nos依赖性到H2O2依赖性的FMD转换，抑制微血管剪切诱导的自噬通量和NO的产生，增加线粒体H2O2的产生。自噬激活可以恢复TERT突变大鼠no介导的扩张，并增强剪切诱导的自噬通量。我们提供的证据表明，自噬对于TERT在维持微血管功能方面的有益作用是必要的，将这一途径定位为通过挽救由TERT信号丧失引起的内皮功能障碍来维持微血管健康的可修改靶标。

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引用次数: 0

Single cell and spatial transcriptomic profiling of the type 2 diabetic coronary microcirculation and myocardium. 2型糖尿病冠状动脉微循环和心肌的单细胞和空间转录组学分析。

IF 9.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Basic Research in Cardiology

Pub Date : 2025-11-07 DOI: 10.1007/s00395-025-01144-7

Patricia E McCallinhart,Corinne H Strawser,Elizabeth A R Garfinkle,Jaye B Navarro,Cynthia McAllister,Tatyana A Vetter,Pamela A Lucchesi,Elaine R Mardis,Louisa Mezache,Rengasayee Veeraraghavan,Katherine E Miller,Aaron J Trask

Coronary microvascular disease (CMD) is an early complication of type 2 diabetes (T2D) involving adverse endothelial and smooth muscle function, vascular remodeling, and alterations in mechanics. These culminate in impaired coronary blood flow. To interrogate transcriptional differences potentially contributing to CMD, we tested the hypothesis that comprehensive single-cell and spatial transcriptomic profiling of the coronary microcirculation and surrounding myocardium will identify new pathways to target in CMD. We utilized an innovative combination of single-cell RNA profiling and spatial transcriptomics to examine transcriptional differences and molecular signatures of CMD in T2D mice. Single-cell RNA profiling and spatial transcriptomics revealed an upregulation of genes linked to adipogenesis, fatty acid metabolism, and oxidative phosphorylation in T2D cell clusters and coronary microvascular-enriched regions. In ECs, VSMCs, cardiomyocyte clusters, fibroblasts, and macrophages, the upregulation of adipogenesis was directed by Angplt4 and Ephx2, whereas Hmgcs2 and Acot2 were the key players in the upregulation of fatty acid metabolism, and Pdk4 and Ech1 were the drivers of oxidative phosphorylation upregulation. These intriguing data support the well-documented concept that cardiac metabolic inflexibility in T2D heart failure-characterized by reduced mitochondrial function, increased reliance on fatty acid oxidation, and impaired glucose utilization-contributes to oxidative stress and lipotoxicity. Our data unveiled novel and unique gene expression signatures of coronary microvessels in the presence and absence of diabetes.

冠状动脉微血管疾病（CMD）是2型糖尿病（T2D）的早期并发症，涉及内皮和平滑肌功能不良、血管重构和力学改变。最终导致冠状动脉血流受损。为了探究可能导致CMD的转录差异，我们测试了一个假设，即冠状动脉微循环和周围心肌的综合单细胞和空间转录组学分析将确定CMD的新靶标途径。我们利用单细胞RNA谱和空间转录组学的创新组合来检测T2D小鼠CMD的转录差异和分子特征。单细胞RNA谱和空间转录组学显示，在T2D细胞簇和冠状动脉微血管富集区，与脂肪形成、脂肪酸代谢和氧化磷酸化相关的基因上调。在内皮细胞、VSMCs、心肌细胞簇、成纤维细胞和巨噬细胞中，脂肪生成的上调是由Angplt4和Ephx2引导的，而Hmgcs2和Acot2是脂肪酸代谢上调的关键参与者，Pdk4和Ech1是氧化磷酸化上调的驱动因素。这些有趣的数据支持了一个有充分文献记载的概念，即T2D心力衰竭的心脏代谢不灵活性——以线粒体功能降低、对脂肪酸氧化的依赖增加和葡萄糖利用受损为特征——有助于氧化应激和脂肪毒性。我们的数据揭示了在存在和不存在糖尿病的情况下冠状动脉微血管的新颖和独特的基因表达特征。

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引用次数: 0

The role of NO, H2O2, and non-NO/H2O2 mechanisms in acetylcholine (ACh)-induced dilation of human arterioles in the absence and presence of coronary artery disease. NO、H2O2和非NO/H2O2机制在乙酰胆碱（ACh）诱导的冠状动脉疾病无和存在的人小动脉扩张中的作用

IF 9.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Basic Research in Cardiology

Pub Date : 2025-11-01 DOI: 10.1007/s00395-025-01143-8

Kostiantyn Drachuk,Yoshinori Nishijima,Aravind Parthasarathy,Yangjing Xie,Sneha Nagavally,Aprill Dawson,David D Gutterman,David X Zhang

This study defines the mechanisms of vasodilation to acetylcholine (ACh) in arterioles from patients with and without coronary artery disease (CAD). Human adipose arterioles (HAA) dissected from discarded surgical samples were cannulated and pressurized at 60 mmHg for measurement of diameter changes by videomicroscopy. No difference in baseline dose response to ACh was observed between non-CAD and CAD patients. L-NAME, NO synthase inhibitor, reduced dilation in both groups but to a greater extent in non-CAD. Peg-CAT, H2O2 scavenger, attenuated response to ACh in non-CAD but not in CAD. Inhibition of NOX4 reduced dilation in non-CAD, whereas NOX2 inhibition attenuated dilation in CAD. The SOD mimetic tempol partially normalized the NO- and H2O2-dependent dilation in CAD arterioles. EPR spin trapping indicated that absolute NO signal after ACh + A-23187 stimulation was higher in non-CAD than in CAD arteries. Western blot analysis revealed higher expression of monomeric eNOS but lower expression of dimeric eNOS and phosphorylated eNOS at Ser-1177 in CAD arteries. Finally, we found higher mRNA and protein expression of NOX2 in CAD arteries. These results provide new evidence that in normal human arterioles, both NO and H2O2 significantly contribute to ACh dilation, with substantial involvement of NOX4 in the H2O2-mediated response. In CAD, the contribution of both NO and H2O2 is diminished, while an NO/H2O2-independent hyperpolarizing pathway becomes predominant. Mechanistically, the NOX4-to-NOX2 switch may play a key role in mediating the change of vasodilator mechanisms in human arterioles during CAD.

本研究确定了冠心病（CAD）患者和非冠心病患者小动脉对乙酰胆碱（ACh）血管舒张的机制。从丢弃的手术样本中剥离的人脂肪小动脉（HAA）插管并加压至60 mmHg，通过视频显微镜测量其直径变化。非CAD和CAD患者对乙酰胆碱的基线剂量反应无差异。L-NAME， NO合成酶抑制剂，在两组中均能降低舒张，但在非cad组中更大程度上。Peg-CAT， H2O2清除剂，在非CAD中对ACh的反应减弱，而在CAD中没有。NOX4抑制可降低非CAD患者的扩张，而NOX2抑制可减弱CAD患者的扩张。SOD模拟tempol部分正常化了CAD小动脉中NO和h2o2依赖性的扩张。EPR自旋捕获表明，ACh + A-23187刺激后，非冠心病动脉的绝对NO信号高于冠心病动脉。Western blot分析显示，在CAD动脉Ser-1177处，单体eNOS表达较高，二聚体eNOS和磷酸化eNOS表达较低。最后，我们发现冠心病动脉中NOX2的mRNA和蛋白表达较高。这些结果提供了新的证据，证明在正常的人小动脉中，NO和H2O2都能显著促进乙酰胆碱扩张，而NOX4在H2O2介导的反应中有重要作用。在CAD中，NO和H2O2的作用减弱，而不依赖于NO/H2O2的超极化途径成为主导。从机制上讲，nox4 - nox2开关可能在CAD期间介导人小动脉血管舒张机制的变化中发挥关键作用。

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引用次数: 0