Endothelial-specific SR-B1 deficiency exacerbates cardiac pathological remodeling and diastolic dysfunction in HFpEF by driving CXCL10 secretion and CXCR3-positive T-cell cardiotropism.
Does endothelial SR-B1 reconstitution prevent cardiac pathological remodeling and diastolic dysfunction in HFpEF models?
This study identifies the SR-B1-CXCL10-CXCR3 axis in cardiac microvascular endothelial cells as a key mediator of HFpEF pathogenesis, offering a novel mechanistic target.
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.
Wu et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF). Endothelial-specific SR-B1 deficiency and SR-B1 reconstitution vs. Wild-type / Control mice was evaluated on Cardiac diastolic dysfunction and pathological remodeling. Endothelial-specific SR-B1 deficiency exacerbates cardiac pathological remodeling and diastolic dysfunction in HFpEF by driving CXCL10 secretion and CXCR3-positive T-cell cardiotropism.