Mechanism of Blood-Heart-Barrier Leakage: Implications for COVID-19 Induced Cardiovascular Injury.
Mechanism of Blood-Heart-Barrier Leakage: Implications for COVID-19 Induced Cardiovascular Injury.
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血心渗漏的机理泄漏：对1900诱导心血管损伤的影响。
DOI：
10.3390/ijms222413546
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发表时间：
2021-12-17
影响因子：
5.6
通讯作者：
Tyagi SC
中科院分区：
文献类型：
--
作者：
Homme RP;George AK;Singh M;Smolenkova I;Zheng Y;Pushpakumar S;Tyagi SC
尽管血心屏障（BHB）渗漏是充血性（心肺）心力衰竭（CHF）的标志，而充血性（心肺）心力衰竭（CHF）是老年人死亡的主要原因，并且是由新型冠状病毒变种（例如严重急性呼吸综合征新型冠状病毒2（SARS-CoV-2），称为COVID-19）引起的病毒性心肌炎，但其机制尚不清楚。该项目的目标是确定 BHB 在 CHF 中的作用机制。心内膜内皮 (EE) 是防止血液从心内膜渗漏到间质的 BHB；然而，这个 BHB 在 CHF 期间被打破。我们实验室和其他实验室之前的研究表明，CHF 期间基质金属蛋白酶 9 (MMP-9) 会被强烈激活。 MMP-9 会降解连接蛋白，导致 EE 功能障碍。我们证明了 EE 与肌细胞和线粒体 (Mito) 的近分泌耦合，但其工作原理仍然悬而未决。为了测试 MMP-9 的激活是否会导致 EE 屏障功能障碍，我们假设如果是这种情况，那么羟氯喹 (HCQ) 治疗实际上可以抑制 MMP-9，从而保留 EE 屏障/近分泌信号传导和同步内皮-肌细胞耦合。为了确定这一点，利用小鼠作为模型系统，通过主动脉-腔静脉瘘 (AVF) 创建 CHF。假手术小鼠和 AVF 小鼠用 HCQ 治疗。测量了心脏肥大、组织重塑诱导的线粒体肌细胞和内皮肌细胞收缩。使用 FITC-白蛋白缀合物测量微血管渗漏。通过超声心动图（Echo）测量心脏功能。结果表明，MMP-9 激活、心内膜内皮渗漏、内皮-肌细胞 (E-M) 解偶联、不同步线粒体融合裂变（Mfn2/Drp1 比值）和线粒体-肌细胞解偶联在 AVF 心力衰竭中非常普遍；然而，HCQ 治疗成功地减轻了 CHF 期间的一些有害的心脏改变。这些发现与人类受试者中 COVID-19 持续并发症引起的各种心脏表现以及由此产生的表型直接相关。
Although blood–heart-barrier (BHB) leakage is the hallmark of congestive (cardio-pulmonary) heart failure (CHF), the primary cause of death in elderly, and during viral myocarditis resulting from the novel coronavirus variants such as the severe acute respiratory syndrome novel corona virus 2 (SARS-CoV-2) known as COVID-19, the mechanism is unclear. The goal of this project is to determine the mechanism of the BHB in CHF. Endocardial endothelium (EE) is the BHB against leakage of blood from endocardium to the interstitium; however, this BHB is broken during CHF. Previous studies from our laboratory, and others have shown a robust activation of matrix metalloproteinase-9 (MMP-9) during CHF. MMP-9 degrades the connexins leading to EE dysfunction. We demonstrated juxtacrine coupling of EE with myocyte and mitochondria (Mito) but how it works still remains at large. To test whether activation of MMP-9 causes EE barrier dysfunction, we hypothesized that if that were the case then treatment with hydroxychloroquine (HCQ) could, in fact, inhibit MMP-9, and thus preserve the EE barrier/juxtacrine signaling, and synchronous endothelial-myocyte coupling. To determine this, CHF was created by aorta-vena cava fistula (AVF) employing the mouse as a model system. The sham, and AVF mice were treated with HCQ. Cardiac hypertrophy, tissue remodeling-induced mitochondrial-myocyte, and endothelial-myocyte contractions were measured. Microvascular leakage was measured using FITC-albumin conjugate. The cardiac function was measured by echocardiography (Echo). Results suggest that MMP-9 activation, endocardial endothelial leakage, endothelial-myocyte (E-M) uncoupling, dyssynchronous mitochondrial fusion-fission (Mfn2/Drp1 ratio), and mito-myocyte uncoupling in the AVF heart failure were found to be rampant; however, treatment with HCQ successfully mitigated some of the deleterious cardiac alterations during CHF. The findings have direct relevance to the gamut of cardiac manifestations, and the resultant phenotypes arising from the ongoing complications of COVID-19 in human subjects.
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DOI：
10.1016/bs.pmbts.2017.02.001
发表时间：
2017
影响因子：
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作者：
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通讯作者：
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