SARS-CoV-2 Spike Protein Exacerbates Thromboembolic Cerebrovascular Complications in Humanized ACE2 Mouse Model

SARS-CoV-2刺突蛋白加剧人源化ACE2小鼠模型的血栓栓塞性脑血管并发症

COVID-19 increases the risk for acute ischemic stroke, yet the molecular mechanisms are unclear and remain unresolved medical challenges. We hypothesize that the SARS-CoV-2 spike protein exacerbates stroke and cerebrovascular complications by increasing coagulation and decreasing fibrinolysis by disrupting the renin-angiotensin-aldosterone system (RAAS).A thromboembolic model was induced in humanized ACE2 knock-in mice after one week of SARS-CoV-2 spike protein injection. hACE2 mice were treated with Losartan, an angiotensin receptor (AT1R) blocker, immediately after spike protein injection. SARS-CoV-2 spike protein exacerbates inflammation and hypercoagulation, leading to increased neurovascular damage and cognitive dysfunction. However, the AT1R blocker, Losartan, restored the RAAS balance and reduced COVID-19-induced thromboembolic cerebrovascular complications.

新型冠状病毒肺炎增加了急性缺血性卒中的风险，但其分子机制尚不清楚，仍然是尚未解决的医学挑战。我们假设SARS-CoV-2刺突蛋白通过破坏肾素-血管紧张素-醛固酮系统 (RAAS) 增加凝血和减少纤维蛋白溶解而加剧卒中和脑血管并发症。在SARS-CoV-2刺突蛋白注射一周后，在人源化ACE2敲入小鼠中诱导血栓栓塞模型。用血管紧张素受体 (AT1R) 阻滞剂氯沙坦治疗hACE2小鼠，刺突蛋白注射后立即。SARS-CoV-2刺突蛋白加剧炎症和高凝状态，导致神经血管损伤和认知功能障碍增加。然而，AT1R阻滞剂氯沙坦恢复了RAAS平衡并减少了COVID-19-induced血栓栓塞性脑血管并发症。

REF: Heath SP, Hermanns VC, Coucha M, Abdelsaid M. SARS-CoV-2 Spike Protein Exacerbates Thromboembolic Cerebrovascular Complications in Humanized ACE2 Mouse Model. Transl Stroke Res. Published online October 2, 2024. doi:10.1007/s12975-024-01301-5 PMID: 39354270

Genome-Wide DNA Methylation Profiling Reveals Low Methylation Variability in Moyamoya Disease

全基因组DNA甲基化分析揭示了烟雾病的低甲基化变异性

Moyamoya disease (MMD) is a chronic cerebrovascular disorder that can lead to stroke and neurological dysfunctions. Given the largely sporadic nature and the role of gene-environment interactions in various diseases, we examined epigenetic modifications in MMD. We performed genome-wide DNA methylation using Illumina 850 K Methylation EPIC BeadChip in two racially distinct adult female cohorts: a non-Asian cohort and an Asian cohort. Our findings revealed strikingly low DNA methylation variability between MMD patients and healthy controls in both female cohorts, with similar reduced variability in the external cohort. This reduced methylation variability in MMD may hinder patients' adaptability to environmental shifts, such as hemodynamic stress, thereby influencing vascular homeostasis and contributing to MMD pathology. These findings offer new insights into the mechanisms of MMD and potential treatment strategies.

烟雾病 (MMD) 是一种慢性脑血管疾病，可导致卒中和神经功能障碍。鉴于在各种疾病中基因与环境相互作用的主要散发性和作用，我们检查了MMD中的表观遗传修饰。我们使用Illumina 850 K甲基化EPIC BeadChip在两个种族不同的成年女性队列中进行了全基因组DNA甲基化: 一个非亚洲队列和一个亚洲队列。我们的研究结果显示，在两个女性队列中，MMD患者和健康对照之间的DNA甲基化变异性都非常低，而在外部队列中变异性的降低相似。MMD中这种降低的甲基化变异性可能会阻碍患者对环境变化的适应性，例如血液动力学压力，从而影响血管稳态并促进MMD病理。这些发现为MMD的机制和潜在的治疗策略提供了新的见解。

REF: Tokairin K, Ito M, Lee AG, et al. Genome-Wide DNA Methylation Profiling Reveals Low Methylation Variability in Moyamoya Disease. Transl Stroke Res. Published online October 2, 2024. doi:10.1007/s12975-024-01299-w PMID: 39356405

The Role of Complement C1qa in Experimental Intracerebral Hemorrhage

补体C1qa在实验性脑出血中的作用

Evidence indicates that the complement system is activated and plays a role in brain injury after intracerebral hemorrhage (ICH). Most studies have focused on the role of C3, C5, and the membrane attack complex. The purpose of this study was to investigate the potential impact of complement C1q, a key upstream component of the classical pathway, on ICH-induced brain injury. Wild-type (WT) and C1qa knock out (KO) mice were compared using an autologous blood injection ICH model.C1qa knockout has beneficial and detrimental effects on ICH-induced brain injury mechanisms, but a consistent beneficial effect after thrombin injection. Strategies to balance the roles of C1q after ICH may represent a promising therapeutic direction.

有证据表明，补体系统被激活并在脑出血 (ICH) 后的脑损伤中起作用。大多数研究都集中在C3，C5和膜攻击复合物的作用上。这项研究的目的是研究补体C1q的潜在影响，补体C1q是经典途径的关键上游成分，对ICH诱导的脑损伤。使用自体血液注射ICH模型比较野生型 (WT) 和C1qa敲除 (KO) 小鼠。C1qa敲除对ICH诱导的脑损伤机制具有有益的和有害的作用，但在凝血酶注射后具有一致的有益作用。ICH后平衡C1q作用的策略可能代表了有希望的治疗方向。

REF: Fu X, Ye F, Wan Y, Xi G, Hua Y, Keep RF. The Role of Complement C1qa in Experimental Intracerebral Hemorrhage. Transl Stroke Res. Published online October 7, 2024. doi:10.1007/s12975-024-01302-4 PMID: 39370487

Impact of Surgical Revascularization on Regression of Enlarged Perivascular Spaces in Adult Moyamoya Disease

手术血运重建对成人烟雾病扩大血管周围间隙消退的影响

Previous studies have suggested that enlarged perivascular spaces (EPVSs) are potential radiological markers of cerebral ischemia in moyamoya disease (MMD). However, serial changes in EPVSs after surgical revascularization have not yet been clarified. We aimed to elucidate the postoperative changes in EPVSs in adult patients with MMD, clinical and radiological factors affecting the number of EPVSs, and the degree of postoperative changes. The number of EPVSs in the centrum semiovale was closely associated with age, PCA involvement, and CBF impairment in adult patients with MMD, which remarkably regressed after surgical revascularization, especially in the hemispheres with PCA involvement and CBF impairment. EPVSs are reversible radiological markers reflecting impaired cerebral hemodynamics in adult patients with MMD.

先前的研究表明，血管周围间隙扩大 (EPVSs) 是烟雾病 (MMD) 中脑缺血的潜在放射学标志物。然而，手术血运重建后EPVSs的系列变化尚未阐明。我们旨在阐明成年MMD患者术后EPVSs的变化，影响EPVSs数量的临床和放射学因素以及术后变化的程度。在成年MMD患者中，中心半卵的EPVSs数量与年龄，PCA受累和CBF损伤密切相关，在手术血运重建后明显消退，尤其是在PCA受累和CBF损伤的半球。EPVSs是反映成年MMD患者脑血流动力学受损的可逆放射学标志物。

REF: Yamamoto S, Akai T, Kashiwazaki D, et al. Impact of Surgical Revascularization on Regression of Enlarged Perivascular Spaces in Adult Moyamoya Disease. Transl Stroke Res. Published online October 8, 2024. doi:10.1007/s12975-024-01303-3 PMID: 39378015