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

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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.
Funding Information
  • National Key Research and Development Program of China (2023YFA1800904)
  • National Key Research and Development Program of China (2025ZD0549600)
  • National Natural Science Foundation of China (U25A2011)
  • the Natural Science Foundation of Beijing, China (L232031)
  • the Natural Science Foundation of Beijing, China (7242163)
  • fundamental research funds for the central universities, peking university medicine sailing program for young scholars's scientific & technological innovation (BMU2023YFJHPY027)
  • National Natural Science Foundation of China (81870364)
  • Guangdong Pharmaceutical University Shenzhen Hospital (Longgang) and Guangdong Pharmaceutical University (LGSY 202302)
  • Special Fund for Medical and Health Technology Innovation Projects, Longgang District Science andTechnology Innovation Program, Shenzhen (LGKCYLWS2022035)
  • Special Fund for Medical and Health Technology Innovation Projects, Longgang District Science andTechnology Innovation Program, Shenzhen (LGKCYLWS2025-34)
  • Special Fund for Medical and Health Technology Innovation Projects, Longgang District Science andTechnology Innovation Program, Shenzhen (LGWJ2024-93)
  • Key Medical Discipline Construction Site in Longgang District
  • National Natural Science Foundation of China (82201314)
  • Fundamental Research Funds for the Central Universities starting fund (BMU2022RCZX038)
  • China Postdoctoral Science Foundation (NO.2021M691944)
  • Natural Science Foundation of Shandong Province (ZR2022MH052)
  • National Natural Science Foundation of China (U22A20286)
  • the Natural Science Foundation of Beijing, China (J230039)

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