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

Yufei, Wu, Xiaomei, Yang, Yu, Bai, Chenze, Li, Peng, Wang, Qing, Xu, Hui, Li, Xiaoli, Rao, Yangkai, Xu, Jie, Chen, Huanhuan, Cao, Qi, Zhang, Mingming, Zhao, Rui, Zhan, Xue, Fan, Yuedong, Hou, Jie, Liu, Hong S., Lu, Tianyun, Wang, Wei Dong, Gao, Linzhang, Huang, Han, Xiao, Lingyun, Zu, Alan, Daugherty, Mingguo, Xu, Lemin, Zheng

EMBO Molecular Medicine |

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.