Microvascular endothelial scavenger receptor class B type I protects against heart failure with preserved ejection fraction by inhibiting T-cell cardiotropism

Authors

• Yufei Wu, Peking University Health Science Center
• Xiaomei Yang, Qilu Hospital of Shandong University
• Yu Bai, Qilu Hospital of Shandong University
• Chenze Li, Wuhan University
• Peng Wang, Peking University
• Qing Xu, Capital Medical University
• Hui Li, Peking University
• Xiaoli Rao, Peking University Health Science Center
• Yangkai Xu, Peking University Health Science Center
• Jie Chen, Peking University Health Science Center
• Huanhuan Cao, Peking University Health Science Center
• Qi Zhang, Peking University Health Science Center
• Mingming Zhao, Peking University
• Rui Zhan, University of Health and Rehabilitation Sciences
• Xue Fan, Shanghai Jiao Tong University
• Yuedong Hou, Qilu Hospital of Shandong University
• Jie Liu, Tongji University School of Medicine
• Hong S. Lu, University of KentuckyFollow
• Tianyun Wang, Peking University Health Science Center
• Wei Dong Gao, Johns Hopkins University School of Medicine
• Linzhang Huang, Fudan University
• Han Xiao, Peking University
• Lingyun Zu, Peking University
• Alan Daugherty, University of KentuckyFollow
• Mingguo Xu, Shantou UniversityFollow
• Lemin Zheng, Peking University Health Science CenterFollow

Abstract

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.

Document Type

Article

Publication Date

5-15-2026

Notes/Citation Information

Publisher Copyright: © The Author(s) 2026.

Digital Object Identifier (DOI)

10.1038/s44321-026-00405-9

Archival?

Archival

Repository Citation

Wu, Yufei; Yang, Xiaomei; Bai, Yu; Li, Chenze; Wang, Peng; Xu, Qing; Li, Hui; Rao, Xiaoli; Xu, Yangkai; Chen, Jie; Cao, Huanhuan; Zhang, Qi; Zhao, Mingming; Zhan, Rui; Fan, Xue; Hou, Yuedong; Liu, Jie; Lu, Hong S.; Wang, Tianyun; Gao, Wei Dong; Huang, Linzhang; Xiao, Han; Zu, Lingyun; Daugherty, Alan; Xu, Mingguo; and Zheng, Lemin, "Microvascular endothelial scavenger receptor class B type I protects against heart failure with preserved ejection fraction by inhibiting T-cell cardiotropism" (2026). Physiology Faculty Publications. 204.
https://uknowledge.uky.edu/physiology_facpub/204