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Spatial Transcriptional Mapping Reveals Site-Specific Pathways Underlying Human Atherosclerotic Plaque Rupture

Sun, Jiangming LU orcid ; Singh, Pratibha LU ; Shami, Annelie LU orcid ; Kluza, Ewelina ; Pan, Mengyu LU orcid ; Djordjevic, Djordje ; Michaelsen, Natasha Barascuk ; Kennbäck, Cecilia LU ; van der Wel, Nicole N. and Orho-Melander, Marju LU , et al. (2023) In Journal of the American College of Cardiology 81(23). p.2213-2227
Abstract

Background: Atherosclerotic plaque ruptures, triggered by blood flow–associated biomechanical forces, cause most myocardial infarctions and strokes. Objectives: This study aims to investigate the exact location and underlying mechanisms of atherosclerotic plaque ruptures, identifying therapeutic targets against cardiovascular events. Methods: Histology, electron microscopy, bulk and spatial RNA sequencing on human carotid plaques were studied in proximal, most stenotic, and distal regions along the longitudinal blood flow direction. Genome-wide association studies were used to examine heritability enrichment and causal relationships of atherosclerosis and stroke. Associations between top differentially expressed genes (DEGs) and... (More)

Background: Atherosclerotic plaque ruptures, triggered by blood flow–associated biomechanical forces, cause most myocardial infarctions and strokes. Objectives: This study aims to investigate the exact location and underlying mechanisms of atherosclerotic plaque ruptures, identifying therapeutic targets against cardiovascular events. Methods: Histology, electron microscopy, bulk and spatial RNA sequencing on human carotid plaques were studied in proximal, most stenotic, and distal regions along the longitudinal blood flow direction. Genome-wide association studies were used to examine heritability enrichment and causal relationships of atherosclerosis and stroke. Associations between top differentially expressed genes (DEGs) and preoperative and postoperative cardiovascular events were examined in a validation cohort. Results: In human carotid atherosclerotic plaques, ruptures predominantly occurred in the proximal and most stenotic regions but not in the distal region. Histologic and electron microscopic examination showed that proximal and most stenotic regions exhibited features of plaque vulnerability and thrombosis. RNA sequencing identified DEGs distinguishing the proximal and most stenotic regions from the distal region which were deemed as most relevant to atherosclerosis-associated diseases as shown by heritability enrichment analyses. The identified pathways associated with the proximal rupture-prone regions were validated by spatial transcriptomics, firstly in human atherosclerosis. Of the 3 top DEGs, matrix metallopeptidase 9 emerged particularly because Mendelian randomization suggested that its high circulating levels were causally associated with atherosclerosis risk. Conclusions: Our findings show plaque site–specific transcriptional signatures associated with proximal rupture-prone regions of carotid atherosclerotic plaques. This led to the geographical mapping of novel therapeutic targets, such as matrix metallopeptidase 9, against plaque rupture.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Atherosclerosis, Mendelian randomization, RNA sequencing, spatial transcriptomics, vulnerable plaques
in
Journal of the American College of Cardiology
volume
81
issue
23
pages
2213 - 2227
publisher
Elsevier
external identifiers
  • pmid:37286250
  • scopus:85160097396
ISSN
0735-1097
DOI
10.1016/j.jacc.2023.04.008
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2023 American College of Cardiology Foundation
id
1cc94edc-a133-444e-837d-35d30aeaf06d
date added to LUP
2023-06-13 20:46:35
date last changed
2024-04-19 23:51:24
@article{1cc94edc-a133-444e-837d-35d30aeaf06d,
  abstract     = {{<p>Background: Atherosclerotic plaque ruptures, triggered by blood flow–associated biomechanical forces, cause most myocardial infarctions and strokes. Objectives: This study aims to investigate the exact location and underlying mechanisms of atherosclerotic plaque ruptures, identifying therapeutic targets against cardiovascular events. Methods: Histology, electron microscopy, bulk and spatial RNA sequencing on human carotid plaques were studied in proximal, most stenotic, and distal regions along the longitudinal blood flow direction. Genome-wide association studies were used to examine heritability enrichment and causal relationships of atherosclerosis and stroke. Associations between top differentially expressed genes (DEGs) and preoperative and postoperative cardiovascular events were examined in a validation cohort. Results: In human carotid atherosclerotic plaques, ruptures predominantly occurred in the proximal and most stenotic regions but not in the distal region. Histologic and electron microscopic examination showed that proximal and most stenotic regions exhibited features of plaque vulnerability and thrombosis. RNA sequencing identified DEGs distinguishing the proximal and most stenotic regions from the distal region which were deemed as most relevant to atherosclerosis-associated diseases as shown by heritability enrichment analyses. The identified pathways associated with the proximal rupture-prone regions were validated by spatial transcriptomics, firstly in human atherosclerosis. Of the 3 top DEGs, matrix metallopeptidase 9 emerged particularly because Mendelian randomization suggested that its high circulating levels were causally associated with atherosclerosis risk. Conclusions: Our findings show plaque site–specific transcriptional signatures associated with proximal rupture-prone regions of carotid atherosclerotic plaques. This led to the geographical mapping of novel therapeutic targets, such as matrix metallopeptidase 9, against plaque rupture.</p>}},
  author       = {{Sun, Jiangming and Singh, Pratibha and Shami, Annelie and Kluza, Ewelina and Pan, Mengyu and Djordjevic, Djordje and Michaelsen, Natasha Barascuk and Kennbäck, Cecilia and van der Wel, Nicole N. and Orho-Melander, Marju and Nilsson, Jan and Formentini, Ivan and Conde-Knape, Karin and Lutgens, Esther and Edsfeldt, Andreas and Gonçalves, Isabel}},
  issn         = {{0735-1097}},
  keywords     = {{Atherosclerosis; Mendelian randomization; RNA sequencing; spatial transcriptomics; vulnerable plaques}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{23}},
  pages        = {{2213--2227}},
  publisher    = {{Elsevier}},
  series       = {{Journal of the American College of Cardiology}},
  title        = {{Spatial Transcriptional Mapping Reveals Site-Specific Pathways Underlying Human Atherosclerotic Plaque Rupture}},
  url          = {{http://dx.doi.org/10.1016/j.jacc.2023.04.008}},
  doi          = {{10.1016/j.jacc.2023.04.008}},
  volume       = {{81}},
  year         = {{2023}},
}