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Spatial-region-resolved proteomic map reveals mechanism of COVID-19-associated heart injury

ABSTRACT: Coronavirus disease 2019 (COVID-19) induces diverse clinical manifestations accompanied by multi-organ dysfunction. Of these, heart complications are the most life threatening. Direct myocardial and vascular injuries due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drive systemic inflammation, which is the leading cause of acute cardiac injury associated with COVID-19. However, in-depth knowledge of the injury characteristics and quantity of its constituent proteins, as well as specific functions of four heart regions, including two ventricles and atria, is lacking. Here, through a strategy for spatial quantitative proteomics by combining comparative anatomy, laser-capture microdissection, and mass spectrometry, we successfully established a complete region-resolved heart proteome map by myocardia and microvessels from four regions of the hearts. We analyzed the dysfunction of different regions of COVID-19 patients’ native heart tissues in situ with histological examinaton. Focusing on the molecular features of myocardial and microvessel tissues with obvious inflammatory cells, a series of specific molecular dysfunctions of myocardium and microvessel were located in different cardiac regions caused by inflammation. These results could provide guidance for future discovery of improved clinical treatments for heart diseases.

ORGANISM(S): Homo Sapiens

SUBMITTER: Ling Leng

PROVIDER: PXD031249 | iProX | Wed Jan 26 00:00:00 GMT 2022

REPOSITORIES: iProX

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Spatial region-resolved proteome map reveals mechanism of COVID-19-associated heart injury.

Leng Ling L Ma Jie J Zhang Pei-Pei PP Xu Si-Chi SC Li Xiao X Jin Ye Y Cai Jun J Tang Rui R Zhao Lei L He Zhi-Cheng ZC Li Man-Sheng MS Zhang Hui H Zhou Liang-Rui LR Wu Zhi-Hong ZH Li Tian-Ran TR Zhu Yun-Ping YP Wang Yu-Jie YJ Wu Hai-Bo HB Ping Yi-Fang YF Yao Xiao-Hong XH Zhu Chu-Hong CH Guo Hai-Tao HT Tan Le-Yong LY Liang Zhi-Yong ZY Bian Xiu-Wu XW Zhang Shu-Yang SY

Cell reports 20220527 11

Direct myocardial and vascular injuries due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-driven inflammation is the leading cause of acute cardiac injury associated with coronavirus disease 2019 (COVID-19). However, in-depth knowledge of the injury characteristics of the heart affected by inflammation is lacking. In this study, using a quantitative spatial proteomics strategy that combines comparative anatomy, laser-capture microdissection, and histological examinati ...[more]

PMID: 35679865

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Project description:Chronic endotheliitis and various cardiovascular co-morbidities are more likely to develop in patients who are recovering from a post-acute SARS-CoV-2 infection. Despite a growing body of clinical data suggesting that the endothelium could be the cause of both cardiac injury and the multi-organ damage found in COVID-19 patients, there is no clear link between endothelial (EC) dysfunction and increased cardiac risk during long COVID. Here, we studied long COVID-19-associated endotheliitis and its implications on cardiac dysfunction. Thrombotic vascular tissues from long COVID patients were harvested and profiled to identify the different mechanisms of viral-induced EC pathogenesis. Human induced pluripotent stem cell (iPSC)–derived ECs were leveraged to model endotheliitis in-a-dish after exposure to SARS-CoV-2, which showed similar EC dysfunction and upregulation of specific cytokines such as CCL2 and IL6, as seen in the primary ECs of long COVID patients. 3D fabricated cardiac organoids generated from iPSC-ECs and iPSC-derived cardiomyocytes (iPSC-CMs) were utilized to understand the pathological influence of endotheliitis on cardiac dysfunction. Notably, cardiac dysfunction was observed only in cardiac organoids that were fabricated with both iPSC-CMs and iPSC-ECs after exposure to SARS-CoV-2. Simultaneous profiling of chromatin accessibility and gene expression dynamics via integration of ATAC-seq and RNA-seq at a single cell resolution revealed CCL2 as the prime cytokine responsible for the non-endothelial “phenotype switching” and the impending cardiac dysfunction in cardiac organoids. This was further validated by high-throughput proteomics that showed CCL2 to be released only by cardiac organoids that were fabricated with iPSC-CMs and iPSC-ECs after SARS-CoV-2 infection. Lastly, disease modeling of the cardiac organoids as well as exposure of human ACE2 transgenic mice to SARS-CoV-2 spike proteins uncovered a putative mechanism for the cardiac dysfunction involving posttranslational modification of cardiac proteins driven by oxidative stress and inflammation. These results suggest that EC-released cytokines can contribute to the pathogenesis of long COVID-associated cardiac dysfunction, and thus a thorough clinical profiling of vascular health could help identify early signs of heart disease in COVID-19 patients.

Dataset Information

Spatial-region-resolved proteomic map reveals mechanism of COVID-19-associated heart injury

Publications

Spatial region-resolved proteome map reveals mechanism of COVID-19-associated heart injury.

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