Persistent renin-angiotensin system and inflammatory dysregulation following COVID-19 impairs ischemic stroke recovery

IF 4.1 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology Pub Date : 2025-12-01 Epub Date: 2025-11-20 DOI:10.1016/j.yexmp.2025.105009

Amy May Lin Quek , Ooiean Teng , Ju-Hea Park , Bernadette Guek Cheng Er , Erle Chuen Hian Lim , Raymond Chee Seong Seet

{"title":"Persistent renin-angiotensin system and inflammatory dysregulation following COVID-19 impairs ischemic stroke recovery","authors":"Amy May Lin Quek , Ooiean Teng , Ju-Hea Park , Bernadette Guek Cheng Er , Erle Chuen Hian Lim , Raymond Chee Seong Seet","doi":"10.1016/j.yexmp.2025.105009","DOIUrl":null,"url":null,"abstract":"<div><div>Previous studies indicate that stroke recovery is worse in patients with prior COVID-19, suggesting persistent biological perturbations. We investigated lingering renin-angiotensin system (RAS) and inflammatory alterations after COVID-19 to uncover mechanisms driving impaired ischemic stroke recovery. We conducted a prospective observational cohort study comparing clinical and molecular profiles of ischemic stroke patients with and without recent COVID-19 infection to age-matched healthy controls. Plasma angiotensin-(1–7), angiotensin II, and soluble ACE2 were quantified, high-throughput proteomic profiling was performed using the Olink® Explore platform, and RNA sequencing was conducted to identify molecular mechanisms related to COVID-19-associated stroke and stroke outcomes (90-day modified Rankin Scale (mRS)). A total of 189 participants (38 COVID-19-associated stroke, 77 non-COVID-19 stroke, and 74 healthy controls) were enrolled. COVID-19-associated stroke patients exhibited significantly higher proportions of cryptogenic strokes (21.1 % vs 10.4 %), earlier hospital presentation (mean 185 vs 310 min), greater use of endovascular thrombectomy (97.4 % vs. 52.6 %), yet poorer functional outcomes (mRS ≥3) at 3 months (73 % vs. 47 %, all <em>p</em> < 0.05). Both stroke groups showed elevated angiotensin-(1–7) levels compared to controls, but angiotensin II levels were notably higher only in non-COVID-19 stroke patients. Proteomic analysis revealed sustained elevation of interferon-gamma (IFN-γ) signaling in COVID-19-associated stroke patients. Reduced AKT3 levels emerged as a significant predictor of poor outcomes, independent of renin-angiotensin biomarkers (adjusted OR 0.40; 95 % CI 0.16–0.94). Stroke patients with low AKT3 levels and poor outcomes exhibited significant upregulation of ribosomal proteins (RPS15, RPS4X, RPS7, RPS18, RPSA, RPS27A, RPS13, RPS23), reflecting heightened translational stress. Persistent RAS and inflammatory dysregulation following COVID-19 may contribute to worse stroke recovery. Future studies should validate and investigate the therapeutic implications of these findings.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 105009"},"PeriodicalIF":4.1000,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental and molecular pathology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014480025000590","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/11/20 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"PATHOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Previous studies indicate that stroke recovery is worse in patients with prior COVID-19, suggesting persistent biological perturbations. We investigated lingering renin-angiotensin system (RAS) and inflammatory alterations after COVID-19 to uncover mechanisms driving impaired ischemic stroke recovery. We conducted a prospective observational cohort study comparing clinical and molecular profiles of ischemic stroke patients with and without recent COVID-19 infection to age-matched healthy controls. Plasma angiotensin-(1–7), angiotensin II, and soluble ACE2 were quantified, high-throughput proteomic profiling was performed using the Olink® Explore platform, and RNA sequencing was conducted to identify molecular mechanisms related to COVID-19-associated stroke and stroke outcomes (90-day modified Rankin Scale (mRS)). A total of 189 participants (38 COVID-19-associated stroke, 77 non-COVID-19 stroke, and 74 healthy controls) were enrolled. COVID-19-associated stroke patients exhibited significantly higher proportions of cryptogenic strokes (21.1 % vs 10.4 %), earlier hospital presentation (mean 185 vs 310 min), greater use of endovascular thrombectomy (97.4 % vs. 52.6 %), yet poorer functional outcomes (mRS ≥3) at 3 months (73 % vs. 47 %, all p < 0.05). Both stroke groups showed elevated angiotensin-(1–7) levels compared to controls, but angiotensin II levels were notably higher only in non-COVID-19 stroke patients. Proteomic analysis revealed sustained elevation of interferon-gamma (IFN-γ) signaling in COVID-19-associated stroke patients. Reduced AKT3 levels emerged as a significant predictor of poor outcomes, independent of renin-angiotensin biomarkers (adjusted OR 0.40; 95 % CI 0.16–0.94). Stroke patients with low AKT3 levels and poor outcomes exhibited significant upregulation of ribosomal proteins (RPS15, RPS4X, RPS7, RPS18, RPSA, RPS27A, RPS13, RPS23), reflecting heightened translational stress. Persistent RAS and inflammatory dysregulation following COVID-19 may contribute to worse stroke recovery. Future studies should validate and investigate the therapeutic implications of these findings.

Abstract Image

查看原文本刊更多论文

COVID-19后持续肾素-血管紧张素系统和炎症失调损害缺血性卒中恢复

先前的研究表明，先前感染COVID-19的患者中风恢复更差，这表明存在持续的生物学干扰。我们研究了COVID-19后持续存在的肾素-血管紧张素系统（RAS）和炎症改变，以揭示缺血性卒中恢复受损的机制。我们进行了一项前瞻性观察队列研究，比较了近期感染和未感染COVID-19的缺血性卒中患者与年龄匹配的健康对照者的临床和分子特征。定量血浆血管紧张素-(1-7)、血管紧张素II和可溶性ACE2，使用Olink®Explore平台进行高通量蛋白质组学分析，并进行RNA测序以确定与covid -19相关的卒中和卒中结局（90天改良Rankin量表（mRS））相关的分子机制。共纳入189名参与者（38名与covid -19相关的卒中，77名非covid -19卒中和74名健康对照）。与covid -19相关的卒中患者在3个月时表现出更高的隐源性卒中比例（21.1%对10.4%），更早的住院时间（平均185分钟对310分钟），更多的血管内取栓术（97.4%对52.6%），但更差的功能结局（mRS≥3）(73%对47%，均p

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Experimental and molecular pathology 医学-病理学

CiteScore

8.90

自引率

0.00%

发文量

审稿时长

11.5 weeks

期刊介绍： Under new editorial leadership, Experimental and Molecular Pathology presents original articles on disease processes in relation to structural and biochemical alterations in mammalian tissues and fluids and on the application of newer techniques of molecular biology to problems of pathology in humans and other animals. The journal also publishes selected interpretive synthesis reviews by bench level investigators working at the "cutting edge" of contemporary research in pathology. In addition, special thematic issues present original research reports that unravel some of Nature''s most jealously guarded secrets on the pathologic basis of disease. Research Areas include: Stem cells; Neoangiogenesis; Molecular diagnostics; Polymerase chain reaction; In situ hybridization; DNA sequencing; Cell receptors; Carcinogenesis; Pathobiology of neoplasia; Complex infectious diseases; Transplantation; Cytokines; Flow cytomeric analysis; Inflammation; Cellular injury; Immunology and hypersensitivity; Athersclerosis.