Microvascular endothelial scavenger receptor class B type I protects against heart failure with preserved ejection fraction by inhibiting T-cell cardiotropism
Cardiac microvascular endothelial cells (CMECs) dysfunction is a well-recognized mediator of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanism remains unclear. Here we find that scavenger receptor class B type I (SR-B1) is predominantly expressed in CMECs and decreased significantly in HFpEF. Endothelial-specific SR-B1 deficiency exacerbates cardiac pathological remodeling and diastolic dysfunction in HFpEF, which can be prevented by endothelial SR-B1 reconstitution through adeno-associated virus serotype 1 (AAV1)-mediated delivery in endothelial-specific SR-B1-deficient mice. Single-cardiac-endothelial-cell transcriptomics and lineage-tracing system reveal that inflammatory CMECs subcluster activation is responsible for the deteriorating HFpEF progression induced by endothelial SR-B1 loss, rather than endothelial-to-mesenchymal transition. Mechanistically, SR-B1 loss drives increased CXCL10 secretion, which orchestrates CMECs activation and CXCR3-positive T-cell cardiotropism to promote diastolic dysfunction-a process associated with endothelial IRF1 activation. Most importantly, the SR-B1-CXCL10-CXCR3 axis is activated in human HFpEF cardiac tissue, and the elevated CXCL10 level in plasma is independently associated with a higher HFpEF prevalence. This study uncovers that activation of the SR-B1-CXCL10-CXCR3 axis in CMECs aggravates HFpEF pathogenesis through the accumulation of CXCR3-positive T-cells in hearts.
Authors
- Hong Lü (ORCID: https://orcid.org/0000-0002-0577-2558)
- Lingyun Zu (ORCID: https://orcid.org/0000-0001-8026-9496)
- Yuedong Hou
- Chenze Li
- Xiaomei Yang (ORCID: https://orcid.org/0000-0002-4003-469X)
- Alan Daugherty (ORCID: https://orcid.org/0000-0003-2093-3775)
- Mingguo Xu (ORCID: https://orcid.org/0000-0002-8215-7065)
- Yangkai Xu
- Han Xiao (ORCID: https://orcid.org/0000-0003-4124-9411)
- Qi Zhang (ORCID: https://orcid.org/0000-0002-0052-3552)
- Lemin Zheng (ORCID: https://orcid.org/0000-0003-4473-6936)
- Linzhang Huang
- Tianyun Wang (ORCID: https://orcid.org/0000-0002-5179-087X)
- Rui Zhan
- Mingming Zhao (ORCID: https://orcid.org/0000-0002-4158-1652)
- Jie Liu
- Jie Chen
- Qing Xu
- Wei Dong Gao (ORCID: https://orcid.org/0009-0006-3584-2867)
- Xue Fan
- Yufei Wu
- Peng Wang (ORCID: https://orcid.org/0000-0002-3093-4280)
- Xiaoli Rao
- Yu Bai
- Huanhuan Cao
Institutions
- Qingdao University (CN)
- University of Kentucky (US)
- Johns Hopkins University (US)
- Shanghai Jiao Tong University (CN)
- Capital Medical University (CN)
- Peking University (CN)
- Fudan University (CN)
- Johns Hopkins Medicine (US)
- Shantou University (CN)
- Wuhan University (CN)
- Aerospace Center Hospital (CN)
- Chinese Institute for Brain Research (CN)
- Affiliated Hospital of Qingdao University (CN)
- Qingdao Municipal Hospital (CN)
- Zhongnan Hospital of Wuhan University (CN)
- Shanghai East Hospital (CN)
- Shanghai First People's Hospital (CN)
- Institute of Tibetan Plateau Research (CN)
- Peking University Third Hospital (CN)
- Qilu Hospital of Shandong University (CN)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-04-13
- DOI
- https://doi.org/10.1038/s44321-026-00405-9
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Natural Science Foundation of Shandong Province
- Peking University
- Guangdong Pharmaceutical University
- Fundamental Research Funds for the Central Universities