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Ketone body 3-hydroxybutyrate elevates cardiac output through peripheral vasorelaxation and enhanced cardiac contractility. 酮体3-羟基丁酸通过外周血管舒张和增强心脏收缩力来提高心输出量。
IF 9.5 1区 医学 Q1 Medicine Pub Date : 2023-09-09 DOI: 10.1007/s00395-023-01008-y
Casper Homilius, Jacob Marthinsen Seefeldt, Julie Sørensen Axelsen, Tina Myhre Pedersen, Trine Monberg Sørensen, Roni Nielsen, Henrik Wiggers, Jakob Hansen, Vladimir V Matchkov, Hans Erik Bøtker, Ebbe Boedtkjer

The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output and myocardial perfusion without affecting blood pressure in humans, but the cardiovascular sites of action remain obscure. Here, we test the hypothesis in rats that 3-OHB acts directly on the heart to increase cardiac contractility and directly on blood vessels to lower systemic vascular resistance. We investigate effects of 3-OHB on (a) in vivo hemodynamics using echocardiography and invasive blood pressure measurements, (b) isolated perfused hearts in Langendorff systems, and (c) isolated arteries and veins in isometric myographs. We compare Na-3-OHB to equimolar NaCl added to physiological buffers or injection solutions. At plasma concentrations of 2-4 mM in vivo, 3-OHB increases cardiac output (by 28.3±7.8%), stroke volume (by 22.4±6.0%), left ventricular ejection fraction (by 13.3±4.6%), and arterial dP/dtmax (by 31.9±11.2%) and lowers systemic vascular resistance (by 30.6±11.2%) without substantially affecting heart rate or blood pressure. Applied to isolated perfused hearts at 3-10 mM, 3-OHB increases left ventricular developed pressure by up to 26.3±7.4 mmHg and coronary perfusion by up to 20.2±9.5%. Beginning at 1-3 mM, 3-OHB relaxes isolated coronary (EC50=12.4 mM), cerebral, femoral, mesenteric, and renal arteries as well as brachial, femoral, and mesenteric veins by up to 60% of pre-contraction within the pathophysiological concentration range. Of the two enantiomers that constitute racemic 3-OHB, D-3-OHB dominates endogenously; but tested separately, the enantiomers induce similar vasorelaxation. We conclude that increased cardiac contractility and generalized systemic vasorelaxation can explain the elevated cardiac output during 3-OHB administration. These actions strengthen the therapeutic rationale for 3-OHB in heart failure management.

酮体3-羟基丁酸酯(3-OHB)在不影响人体血压的情况下增加心输出量和心肌灌注,但其心血管作用部位仍不清楚。在这里,我们在大鼠中检验了3-OHB直接作用于心脏以增加心脏收缩力和直接作用于血管以降低全身血管阻力的假设。我们研究了3-OHB对(a)使用超声心动图和有创血压测量的体内血液动力学的影响,(b)Langendorff系统中的离体灌注心脏,以及(c)等长肌图中的分离动脉和静脉的影响。我们将Na-3-OHB与添加到生理缓冲液或注射溶液中的等摩尔NaCl进行比较。在体内2-4 mM的血浆浓度下,3-OHB可增加心输出量(28.3±7.8%)、射血容量(22.4±6.0%)、左心室射血分数(13.3±4.6%)和动脉dP/dtmax(31.9±11.2%),并降低全身血管阻力(30.6±11.2%。3-OHB应用于3-10 mM的离体灌注心脏,可使左心室发展压力增加26.3±7.4 mmHg,使冠状动脉灌注增加20.2±9.5%。从1-3 mM开始,3-OHB可放松离体冠状动脉(EC50=12.4 mM)、脑动脉、股动脉、肠系膜动脉和肾动脉,和肠系膜静脉在病理生理浓度范围内收缩前高达60%。在构成外消旋3-OHB的两种对映体中,D-3-OHB内源性占主导地位;但单独测试,对映体诱导类似的血管舒张。我们的结论是,心脏收缩力的增加和全身血管舒张可以解释3-OHB给药期间心输出量的升高。这些作用加强了3-OHB在心力衰竭管理中的治疗原理。
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引用次数: 0
Cardiac fibroblast GSK-3α aggravates ischemic cardiac injury by promoting fibrosis, inflammation, and impairing angiogenesis. 心脏成纤维细胞GSK-3α通过促进纤维化、炎症和损害血管生成加重缺血性心脏损伤。
IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2023-09-01 DOI: 10.1007/s00395-023-01005-1
Prachi Umbarkar, Suma Ejantkar, Sulivette Y Ruiz Ramirez, Angelica Toro Cora, Qinkun Zhang, Sultan Tousif, Hind Lal

Myocardial infarction (MI) is the leading cause of death worldwide. Glycogen synthase kinase-3 (GSK-3) has been considered to be a promising therapeutic target for cardiovascular diseases. GSK-3 is a family of ubiquitously expressed serine/threonine kinases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Previously, our group identified that cardiac fibroblast (FB) GSK-3β acts as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of FB-GSK-3α in MI pathology is not defined. To determine the role of FB-GSK-3α in MI-induced adverse cardiac remodeling, GSK-3α was deleted specifically in the residential fibroblast or myofibroblast (MyoFB) using tamoxifen (TAM) inducible Tcf21 or Periostin (Postn) promoter-driven Cre recombinase, respectively. Echocardiographic analysis revealed that FB- or MyoFB-specific GSK-3α deletion prevented the development of dilative remodeling and cardiac dysfunction. Morphometrics and histology studies confirmed improvement in capillary density and a remarkable reduction in hypertrophy and fibrosis in the KO group. We harvested the hearts at 4 weeks post-MI and analyzed signature genes of adverse remodeling. Specifically, qPCR analysis was performed to examine the gene panels of inflammation (TNFα, IL-6, IL-1β), fibrosis (COL1A1, COL3A1, COMP, Fibronectin-1, Latent TGF-β binding protein 2), and hypertrophy (ANP, BNP, MYH7). These molecular markers were essentially normalized due to FB-specific GSK-3α deletion. Further molecular studies confirmed that FB-GSK-3α could regulate NF-kB activation and expression of angiogenesis-related proteins. Our findings suggest that FB-GSK-3α plays a critical role in the pathological cardiac remodeling of ischemic hearts, therefore, it could be therapeutically targeted.

心肌梗死(MI)是世界范围内导致死亡的主要原因。糖原合成酶激酶-3 (GSK-3)被认为是一种有前景的治疗心血管疾病的靶点。GSK-3是一个普遍表达的丝氨酸/苏氨酸激酶家族。GSK-3亚型似乎在心脏中发挥重叠、独特甚至相反的功能。之前,我们的研究小组发现,心脏成纤维细胞(FB) GSK-3β在缺血心脏中作为纤维化重塑的负调节因子。然而,FB-GSK-3α在心肌梗死病理中的作用尚未明确。为了确定FB-GSK-3α在mi诱导的不良心脏重构中的作用,分别使用他莫昔芬(TAM)诱导的Tcf21或Periostin (Postn)启动子驱动的Cre重组酶,在居住成纤维细胞或肌成纤维细胞(MyoFB)中特异性地删除GSK-3α。超声心动图分析显示FB-或myofb特异性GSK-3α缺失可阻止扩张性重构和心功能障碍的发生。形态计量学和组织学研究证实,KO组毛细血管密度改善,肥厚和纤维化显著减少。我们在心肌梗死后4周采集心脏,分析不良重构的特征基因。具体而言,采用qPCR分析检测炎症(TNFα、IL-6、IL-1β)、纤维化(COL1A1、COL3A1、COMP、Fibronectin-1、Latent TGF-β结合蛋白2)和肥大(ANP、BNP、MYH7)基因组。由于fb特异性GSK-3α缺失,这些分子标记基本上归一化。进一步的分子研究证实FB-GSK-3α可以调节NF-kB的激活和血管生成相关蛋白的表达。我们的研究结果表明FB-GSK-3α在缺血性心脏的病理性心脏重塑中起关键作用,因此可以作为治疗靶点。
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引用次数: 0
Myeloperoxidase is a critical mediator of anthracycline-induced cardiomyopathy. 髓过氧化物酶是蒽环类药物诱导的心肌病的关键介质。
IF 9.5 1区 医学 Q1 Medicine Pub Date : 2023-09-01 DOI: 10.1007/s00395-023-01006-0
Felix Sebastian Nettersheim, Johannes David Schlüter, Wiebke Kreuzberg, Dennis Mehrkens, Simon Grimm, Harshal Nemade, Simon Braumann, Alexander Hof, Henning Guthoff, Vera Peters, Friedrich Felix Hoyer, Yulia Kargapolova, Jan-Wilm Lackmann, Stefan Müller, Christian P Pallasch, Michael Hallek, Agapios Sachinidis, Matti Adam, Holger Winkels, Stephan Baldus, Simon Geißen, Martin Mollenhauer

Cardiotoxicity is a major complication of anthracycline therapy that negatively impacts prognosis. Effective pharmacotherapies for prevention of anthracycline-induced cardiomyopathy (AICM) are currently lacking. Increased plasma levels of the neutrophil-derived enzyme myeloperoxidase (MPO) predict occurrence of AICM in humans. We hypothesized that MPO release causally contributes to AICM. Mice intravenously injected with the anthracycline doxorubicin (DOX) exhibited higher neutrophil counts and MPO levels in the circulation and cardiac tissue compared to saline (NaCl)-treated controls. Neutrophil-like HL-60 cells exhibited increased MPO release upon exposition to DOX. DOX induced extensive nitrosative stress in cardiac tissue alongside with increased carbonylation of sarcomeric proteins in wildtype but not in Mpo-/- mice. Accordingly, co-treatment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with DOX and MPO aggravated loss of hiPSC-CM-contractility compared to DOX treatment alone. DOX-treated animals exhibited pronounced cardiac apoptosis and inflammation, which was attenuated in MPO-deficient animals. Finally, genetic MPO deficiency and pharmacological MPO inhibition protected mice from the development of AICM. The anticancer efficacy of DOX was unaffected by MPO deficiency. Herein we identify MPO as a critical mediator of AICM. We demonstrate that DOX induces cardiac neutrophil infiltration and release of MPO, which directly impairs cardiac contractility through promoting oxidation of sarcomeric proteins, cardiac inflammation and cardiomyocyte apoptosis. MPO thus emerges as a promising pharmacological target for prevention of AICM.

心脏毒性是蒽环类药物治疗的主要并发症,对预后有负面影响。目前缺乏有效的药物治疗来预防蒽环类药物诱导的心肌病(AICM)。中性粒细胞来源的髓过氧化物酶(MPO)的血浆水平升高可预测人类AICM的发生。我们假设MPO的释放是AICM的原因之一。与生理盐水(NaCl)处理的对照组相比,静脉注射蒽环类药物阿霉素(DOX)的小鼠在循环和心脏组织中表现出更高的中性粒细胞计数和MPO水平。中性粒细胞样HL-60细胞在暴露于DOX后表现出MPO释放增加。DOX在野生型小鼠中诱导了心脏组织中广泛的亚硝化应激,同时增加了肌块蛋白的羰基化,但在Mpo-/-小鼠中没有。因此,与单独DOX治疗相比,用DOX和MPO联合治疗人诱导多能干细胞衍生的心肌细胞(hiPSC CM)加重了hiPSC CM收缩性的丧失。DOX处理的动物表现出明显的心脏细胞凋亡和炎症,这在MPO缺乏的动物中减弱。最后,遗传性MPO缺乏和药理学MPO抑制保护小鼠免受AICM的发展。DOX的抗癌功效不受MPO缺乏的影响。在此,我们将MPO确定为AICM的关键介质。我们证明DOX诱导心脏中性粒细胞浸润和MPO的释放,MPO通过促进肌块蛋白的氧化、心脏炎症和心肌细胞凋亡直接损害心脏收缩性。MPO因此成为预防AICM的一个有前景的药理学靶点。
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引用次数: 0
Identification of the specific molecular and functional signatures of pre-beta-HDL: relevance to cardiovascular disease. 前- hdl特异性分子和功能特征的鉴定:与心血管疾病的相关性
IF 9.5 1区 医学 Q1 Medicine Pub Date : 2023-08-28 DOI: 10.1007/s00395-023-01004-2
Isabelle Guillas, Marie Lhomme, Cédric Pionneau, Lucrèce Matheron, Maharajah Ponnaiah, Sophie Galier, Sandrine Lebreton, Marie Delbos, Feng Ma, Maryam Darabi, Petra El Khoury, Marianne Abifadel, Philippe Couvert, Philippe Giral, Philippe Lesnik, Maryse Guerin, Wilfried Le Goff, Anatol Kontush

While low concentrations of high-density lipoprotein-cholesterol (HDL-C) are widely accepted as an independent cardiovascular risk factor, HDL-C-rising therapies largely failed, suggesting the importance of both HDL functions and individual subspecies. Indeed HDL particles are highly heterogeneous, with small, dense pre-beta-HDLs being considered highly biologically active but remaining poorly studied, largely reflecting difficulties for their purification. We developed an original experimental approach allowing the isolation of sufficient amounts of human pre-beta-HDLs and revealing the specificity of their proteomic and lipidomic profiles and biological activities. Pre-beta-HDLs were enriched in highly poly-unsaturated species of phosphatidic acid and phosphatidylserine, and in an unexpectedly high number of proteins implicated in the inflammatory response, including serum paraoxonase/arylesterase-1, vitronectin and clusterin, as well as in complement regulation and immunity, including haptoglobin-related protein, complement proteins and those of the immunoglobulin class. Interestingly, amongst proteins associated with lipid metabolism, phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase were strongly enriched in, or restricted to, pre-beta-HDL. Furthermore, pre-beta-HDL potently mediated cellular cholesterol efflux and displayed strong anti-inflammatory activities. A correlational network analysis between lipidome, proteome and biological activities highlighted 15 individual lipid and protein components of pre-beta-HDL relevant to cardiovascular disease, which may constitute novel diagnostic targets in a pathological context of altered lipoprotein metabolism.

虽然低浓度的高密度脂蛋白-胆固醇(HDL- c)被广泛认为是一个独立的心血管危险因素,但HDL- c升高的治疗在很大程度上失败了,这表明HDL功能和个体亚种的重要性。事实上,高密度脂蛋白颗粒是高度不均匀的,小而致密的前-高密度脂蛋白被认为具有高度的生物活性,但研究很少,这在很大程度上反映了它们的纯化困难。我们开发了一种原始的实验方法,允许分离足够数量的人β - hdl前,并揭示其蛋白质组学和脂质组学特征和生物活性的特异性。前- hdl富含磷脂酸和磷脂酰丝氨酸的高度多不饱和种类,以及与炎症反应相关的大量蛋白质,包括血清对氧磷酶/芳基酯酶-1、玻璃体连接蛋白和聚簇蛋白,以及补体调节和免疫,包括接触珠蛋白相关蛋白、补体蛋白和免疫球蛋白类蛋白质。有趣的是,在与脂质代谢相关的蛋白质中,磷脂转移蛋白、胆固醇酯转移蛋白和卵磷脂:胆固醇酰基转移酶在前- hdl中被强烈富集或限制。此外,前- hdl可有效介导细胞胆固醇外排,并显示出强大的抗炎活性。脂质组、蛋白质组和生物活性之间的相关网络分析强调了与心血管疾病相关的前β - hdl的15个单独的脂质和蛋白质成分,这些成分可能构成脂蛋白代谢改变病理背景下的新诊断靶点。
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引用次数: 0
Preventing mitochondrial reverse electron transport as a strategy for cardioprotection. 防止线粒体反向电子传递作为心脏保护策略。
IF 9.5 1区 医学 Q1 Medicine Pub Date : 2023-08-28 DOI: 10.1007/s00395-023-01002-4
Hiran A Prag, Michael P Murphy, Thomas Krieg

In the context of myocardial infarction, the burst of superoxide generated by reverse electron transport (RET) at complex I in mitochondria is a crucial trigger for damage during ischaemia/reperfusion (I/R) injury. Here we outline the necessary conditions for superoxide production by RET at complex I and how it can occur during reperfusion. In addition, we explore various pathways that are implicated in generating the conditions for RET to occur and suggest potential therapeutic strategies to target RET, aiming to achieve cardioprotection.

在心肌梗死的情况下,线粒体复合体I上逆电子传递(RET)产生的超氧化物爆发是缺血/再灌注(I/R)损伤过程中损伤的关键触发因素。在这里,我们概述了复合体I的RET产生超氧化物的必要条件以及它如何在再灌注过程中发生。此外,我们探索了与RET发生条件产生有关的各种途径,并提出了针对RET的潜在治疗策略,旨在实现心脏保护。
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引用次数: 2
Perspective: mitochondrial STAT3 in cardioprotection. 观点:线粒体STAT3在心脏保护中的作用。
IF 9.5 1区 医学 Q1 Medicine Pub Date : 2023-08-24 DOI: 10.1007/s00395-023-01003-3
Petra Kleinbongard

Activation of signal transducer and activator of transcription 3 (STAT3) has been identified as a key cardioprotective signal not only in animal studies but also in humans-in animals, STAT3 is causally involved in cardioprotection. In response to late ischemic conditioning, canonical function of STAT3 activation upregulates the expression of cardioprotective and anti-apoptotic proteins. In its non-canonical function, STAT3 is activated during ischemic conditioning and is part of the cardioprotective cytosolic survival activating factor enhancement pathway. Activated STAT3 is imported and localized to the mitochondria. Mitochondrial STAT3 stimulates the activity of mitochondrial electron transport chain complex I, reduces mitochondrial reactive oxygen species production and mitochondrial permeability transition pore opening. Finally, two novel aspects of STAT activation in cardioprotection are discussed: a genetic variance of the STAT encoding region as a potential primordial confounding variable for cardioprotection, and the cardioprotective potential of sodium-glucose cotransporter 2 inhibitors through STAT3 activation.

激活信号换能器和转录激活因子3 (STAT3)已被确定为一个关键的心脏保护信号,不仅在动物研究中,而且在人类研究中-在动物中,STAT3参与心脏保护。STAT3激活的典型功能上调了心肌保护蛋白和抗凋亡蛋白的表达。在其非规范功能中,STAT3在缺血条件下被激活,是心脏保护性细胞质存活激活因子增强途径的一部分。激活的STAT3被导入并定位于线粒体。线粒体STAT3刺激线粒体电子传递链复合体I的活性,减少线粒体活性氧的产生和线粒体通透性过渡开孔。最后,本文讨论了STAT激活在心脏保护中的两个新方面:STAT编码区域的遗传变异作为心脏保护的潜在原始混杂变量,以及钠-葡萄糖共转运蛋白2抑制剂通过STAT3激活的心脏保护潜力。
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引用次数: 0
Rivaroxaban attenuates neutrophil maturation in the bone marrow niche. 利伐沙班减弱骨髓生态位中性粒细胞成熟。
IF 9.5 1区 医学 Q1 Medicine Pub Date : 2023-08-14 DOI: 10.1007/s00395-023-01001-5
R Schneckmann, M Döring, S Gerfer, S Gorressen, S Heitmeier, C Helten, A Polzin, C Jung, M Kelm, A C Fender, U Flögel, M Grandoch

Pharmacological inhibition of factor Xa by rivaroxaban has been shown to mediate cardioprotection and is frequently used in patients with, e.g., atrial fibrillation. Rivaroxaban's anti-inflammatory actions are well known, but the underlying mechanisms are still incompletely understood. To date, no study has focused on the effects of rivaroxaban on the bone marrow (BM), despite growing evidence that the BM and its activation are of major importance in the development/progression of cardiovascular disease. Thus, we examined the impact of rivaroxaban on BM composition under homeostatic conditions and in response to a major cardiovascular event. Rivaroxaban treatment of mice for 7 days markedly diminished mature leukocytes in the BM. While apoptosis of BM-derived mature myeloid leukocytes was unaffected, lineage-negative BM cells exhibited a differentiation arrest at the level of granulocyte-monocyte progenitors, specifically affecting neutrophil maturation via downregulation of the transcription factors Spi1 and Csfr1. To assess whether this persists also in situations of increased leukocyte demand, mice were subjected to cardiac ischemia/reperfusion injury (I/R): 7 d pretreatment with rivaroxaban led to reduced cardiac inflammation 72 h after I/R and lowered circulating leukocyte numbers. However, BM myelopoiesis showed a rescue of the leukocyte differentiation arrest, indicating that rivaroxaban's inhibitory effects are restricted to homeostatic conditions and are mainly abolished during emergency hematopoiesis. In translation, ST-elevation MI patients treated with rivaroxaban also exhibited reduced circulating leukocyte numbers. In conclusion, we demonstrate that rivaroxaban attenuates neutrophil maturation in the BM, which may offer a therapeutic option to limit overshooting of the immune response after I/R.

利伐沙班对Xa因子的药理学抑制已被证明可以介导心脏保护,并经常用于心房颤动等患者。利伐沙班的抗炎作用是众所周知的,但其潜在的机制仍然不完全了解。迄今为止,尽管越来越多的证据表明骨髓及其激活在心血管疾病的发生/进展中具有重要意义,但尚未有研究关注利伐沙班对骨髓(BM)的影响。因此,我们研究了利伐沙班在稳态条件下和对主要心血管事件的反应中对脑内膜组成的影响。利伐沙班治疗小鼠7天后,BM中成熟白细胞明显减少。虽然BM来源的成熟髓系白细胞的凋亡不受影响,但谱系阴性BM细胞在粒细胞-单核细胞祖细胞水平上表现出分化停滞,特别是通过下调转录因子Spi1和Csfr1影响中性粒细胞成熟。为了评估这种情况是否在白细胞需求增加的情况下也持续存在,我们对小鼠进行了心脏缺血/再灌注损伤(I/R):用利伐沙班预处理7天,I/R后72小时心脏炎症减轻,循环白细胞数量降低。然而,骨髓生成显示出对白细胞分化停滞的拯救,这表明利伐沙班的抑制作用仅限于稳态条件下,主要在紧急造血时被消除。换句话说,接受利伐沙班治疗的st段抬高心肌梗死患者也表现出循环白细胞数量减少。总之,我们证明利伐沙班可以减弱脑脊髓炎中性粒细胞的成熟,这可能为限制I/R后免疫反应的过调提供了一种治疗选择。
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引用次数: 0
The heterocellular heart: identities, interactions, and implications for cardiology. 异细胞心脏:特性、相互作用及对心脏病学的影响。
IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2023-07-26 DOI: 10.1007/s00395-023-01000-6
Achim Lother, Peter Kohl

The heterocellular nature of the heart has been receiving increasing attention in recent years. In addition to cardiomyocytes as the prototypical cell type of the heart, non-myocytes such as endothelial cells, fibroblasts, or immune cells are coming more into focus. The rise of single-cell sequencing technologies enables  identification of ever more subtle differences and has reignited the question of what defines a cell's identity. Here we provide an overview of the major cardiac cell types, describe their roles in homeostasis, and outline recent findings on non-canonical functions that may be of relevance for cardiology. We highlight modes of biochemical and biophysical interactions between different cardiac cell types and discuss the potential implications of the heterocellular nature of the heart for basic research and therapeutic interventions.

近年来,心脏的异细胞特性日益受到关注。除了作为心脏原型细胞类型的心肌细胞外,内皮细胞、成纤维细胞或免疫细胞等非心肌细胞也越来越受到关注。单细胞测序技术的兴起使人们能够识别更微妙的差异,并再次引发了细胞身份的定义问题。在此,我们概述了主要的心脏细胞类型,描述了它们在体内平衡中的作用,并概述了可能与心脏病学有关的非典型功能的最新发现。我们强调了不同心脏细胞类型之间的生化和生物物理相互作用模式,并讨论了心脏的异细胞特性对基础研究和治疗干预的潜在影响。
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引用次数: 0
Matrix metalloproteinase-2 proteolyzes mitofusin-2 and impairs mitochondrial function during myocardial ischemia-reperfusion injury. 在心肌缺血再灌注损伤过程中,基质金属蛋白酶-2会蛋白水解丝裂蛋白-2并损害线粒体功能。
IF 9.5 1区 医学 Q1 Medicine Pub Date : 2023-07-26 DOI: 10.1007/s00395-023-00999-y
Wesam Bassiouni, Robert Valencia, Zabed Mahmud, John M Seubert, Richard Schulz

During myocardial ischemia and reperfusion (IR) injury matrix metalloproteinase-2 (MMP-2) is rapidly activated in response to oxidative stress. MMP-2 is a multifunctional protease that cleaves both extracellular and intracellular proteins. Oxidative stress also impairs mitochondrial function which is regulated by different proteins, including mitofusin-2 (Mfn-2), which is lost in IR injury. Oxidative stress and mitochondrial dysfunction trigger the NLRP3 inflammasome and the innate immune response which invokes the de novo expression of an N-terminal truncated isoform of MMP-2 (NTT-MMP-2) at or near mitochondria. We hypothesized that MMP-2 proteolyzes Mfn-2 during myocardial IR injury, impairing mitochondrial function and enhancing the inflammasome response. Isolated hearts from mice subjected to IR injury (30 min ischemia/40 min reperfusion) showed a significant reduction in left ventricular developed pressure (LVDP) compared to aerobically perfused hearts. IR injury increased MMP-2 activity as observed by gelatin zymography and increased degradation of troponin I, an intracellular MMP-2 target. MMP-2 preferring inhibitors, ARP-100 or ONO-4817, improved post-ischemic recovery of LVDP compared to vehicle perfused IR hearts. In muscle fibers isolated from IR hearts the rates of mitochondrial oxygen consumption and ATP production were impaired compared to those from aerobic hearts, whereas ARP-100 or ONO-4817 attenuated these reductions. IR hearts showed higher levels of NLRP3, cleaved caspase-1 and interleukin-1β in the cytosolic fraction, while the mitochondria-enriched fraction showed reduced levels of Mfn-2, compared to aerobic hearts. ARP-100 or ONO-4817 attenuated these changes. Co-immunoprecipitation showed that MMP-2 is associated with Mfn-2 in aerobic and IR hearts. ARP-100 or ONO-4817 also reduced infarct size and cell death in hearts subjected to 45 min ischemia/120 min reperfusion. Following myocardial IR injury, impaired contractile function and mitochondrial respiration and elevated inflammasome response could be attributed, at least in part, to MMP-2 activation, which targets and cleaves mitochondrial Mfn-2. Inhibition of MMP-2 activity protects against cardiac contractile dysfunction in IR injury in part by preserving Mfn-2 and suppressing inflammation.

在心肌缺血和再灌注(IR)损伤期间,基质金属蛋白酶-2(MMP-2)在氧化应激的作用下被迅速激活。MMP-2 是一种多功能蛋白酶,可裂解细胞外和细胞内蛋白质。氧化应激也会损害线粒体功能,而线粒体功能由不同的蛋白质调控,其中包括在红外损伤中丢失的丝裂蛋白-2(Mfn-2)。氧化应激和线粒体功能障碍会触发 NLRP3 炎症小体和先天性免疫反应,从而在线粒体或线粒体附近重新表达一种 N 端截短的 MMP-2 异构体(NTT-MMP-2)。我们假设,在心肌红外损伤过程中,MMP-2 会蛋白水解 Mfn-2,从而损害线粒体功能并增强炎性体反应。受到红外损伤(30 分钟缺血/40 分钟再灌注)的小鼠离体心脏显示,与有氧灌注的心脏相比,左心室显影压(LVDP)显著降低。通过明胶酶谱观察到,红外损伤增加了 MMP-2 的活性,并增加了肌钙蛋白 I(细胞内 MMP-2 的靶标)的降解。MMP-2偏好抑制剂ARP-100或ONO-4817可改善缺血后LVDP的恢复,优于药物灌注的红外心脏。与有氧心脏相比,从红外心脏分离出的肌纤维线粒体耗氧率和ATP生成率受到影响,而ARP-100或ONO-4817可减轻这些影响。与有氧心脏相比,红外心脏细胞质部分的 NLRP3、裂解的 Caspase-1 和白细胞介素-1β 水平较高,而线粒体富集部分的 Mfn-2 水平较低。ARP-100或ONO-4817可减轻这些变化。共免疫沉淀显示,在有氧和红外心脏中,MMP-2与Mfn-2相关。ARP-100或ONO-4817还能减少心脏缺血45分钟/再灌注120分钟后的梗死面积和细胞死亡。心肌红外损伤后,收缩功能和线粒体呼吸受损以及炎性体反应升高,至少可部分归因于MMP-2的活化,MMP-2靶向并裂解线粒体Mfn-2。抑制 MMP-2 的活性可保护线粒体 Mfn-2 并抑制炎症反应,从而部分防止红外损伤导致的心脏收缩功能障碍。
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引用次数: 1
Endothelial ILK induces cardioprotection by preventing coronary microvascular dysfunction and endothelial-to-mesenchymal transition. 内皮ILK通过防止冠状动脉微血管功能障碍和内皮-间质转化诱导心脏保护。
IF 9.5 1区 医学 Q1 Medicine Pub Date : 2023-07-14 DOI: 10.1007/s00395-023-00997-0
P Reventun, S Sánchez-Esteban, A Cook-Calvete, M Delgado-Marín, C Roza, S Jorquera-Ortega, I Hernandez, L Tesoro, L Botana, J L Zamorano, C Zaragoza, M Saura

Endothelial dysfunction is an early event in coronary microvascular disease. Integrin-linked kinase (ILK) prevents endothelial nitric oxide synthase (eNOS) uncoupling and, thus, endothelial dysfunction. However, the specific role of endothelial ILK in cardiac function remains to be fully elucidated. We hypothesised that endothelial ILK plays a crucial role in maintaining coronary microvascular function and contractile performance in the heart. We generated an endothelial cell-specific ILK conditional knock-out mouse (ecILK cKO) and investigated cardiovascular function. Coronary endothelial ILK deletion significantly impaired cardiac function: ejection fraction, fractional shortening and cardiac output decreased, whilst left ventricle diastolic internal diameter decreased and E/A and E/E' ratios increased, indicating not only systolic but also diastolic dysfunction. The functional data correlated with extensive extracellular matrix remodelling and perivascular fibrosis, indicative of adverse cardiac remodelling. Mice with endothelial ILK deletion suffered early ischaemic-like events with ST elevation and transient increases in cardiac troponins, which correlated with fibrotic remodelling. In addition, ecILK cKO mice exhibited many features of coronary microvascular disease: reduced cardiac perfusion, impaired coronary flow reserve and arterial remodelling with patent epicardial coronary arteries. Moreover, endothelial ILK deletion induced a moderate increase in blood pressure, but the antihypertensive drug Losartan did not affect microvascular remodelling whilst only partially ameliorated fibrotic remodelling. The plasma miRNA profile reveals endothelial-to-mesenchymal transition (endMT) as an upregulated pathway in endothelial ILK conditional KO mice. Our results show that endothelial cells in the microvasculature in endothelial ILK conditional KO mice underwent endMT. Moreover, endothelial cells isolated from these mice and ILK-silenced human microvascular endothelial cells underwent endMT, indicating that decreased endothelial ILK contributes directly to this endothelial phenotype shift. Our results identify ILK as a crucial regulator of microvascular endothelial homeostasis. Endothelial ILK prevents microvascular dysfunction and cardiac remodelling, contributing to the maintenance of the endothelial cell phenotype.

内皮功能障碍是冠状动脉微血管疾病的早期事件。整合素连接激酶(ILK)可防止内皮一氧化氮合酶(eNOS)解偶联,从而防止内皮功能障碍。然而,内皮细胞ILK在心功能中的具体作用仍有待充分阐明。我们假设内皮细胞ILK在维持心脏冠状动脉微血管功能和收缩性能方面起着至关重要的作用。我们制造了内皮细胞特异性ILK条件敲除小鼠(ecILK cKO)并研究了心血管功能。冠状动脉内皮ILK缺失显著损害心功能:射血分数、分数缩短和心输出量降低,左心室舒张内径减小,E/A和E/E′比值升高,表明不仅有收缩期功能障碍,还有舒张期功能障碍。功能数据与广泛的细胞外基质重构和血管周围纤维化相关,表明不良的心脏重构。内皮细胞ILK缺失的小鼠出现早期缺血样事件,伴有ST段抬高和心脏肌钙蛋白的短暂性增加,这与纤维化重构相关。此外,ecILK cKO小鼠表现出冠状动脉微血管疾病的许多特征:心脏灌注减少,冠状动脉血流储备受损,动脉重构伴心外膜冠状动脉未闭。此外,内皮ILK缺失诱导血压适度升高,但降压药氯沙坦不影响微血管重构,仅部分改善纤维化重构。血浆miRNA谱显示内皮-间质转化(endMT)在内皮ILK条件下的KO小鼠中是一个上调的途径。我们的研究结果表明,内皮ILK条件下的KO小鼠微血管内皮细胞发生了endMT。此外,从这些小鼠和ILK沉默的人微血管内皮细胞分离的内皮细胞发生了endMT,表明内皮ILK的减少直接导致了内皮表型的转变。我们的研究结果确定ILK是微血管内皮稳态的关键调节因子。内皮ILK可防止微血管功能障碍和心脏重构,有助于维持内皮细胞表型。
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引用次数: 0
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Basic Research in Cardiology
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