Study Identifies suPAR Protein as Driver of Heart Failure with Preserved Ejection Fraction
A new preclinical study published on bioRxiv demonstrates that elevated levels of the circulating protein suPAR are sufficient to worsen heart failure with preserved ejection fraction (HFpEF) by priming inflammatory macrophages, not merely by serving as a passive disease marker. Researchers used transgenic mice in a two-hit cardiometabolic model and found that suPAR amplified diastolic dysfunction and pulmonary congestion through expansion of CCR2+ inflammatory monocytes and macrophages, without affecting blood pressure or ejection fraction. The findings convert two decades of epidemiological association into a mechanistic hypothesis and point toward existing clinical-stage anti-suPAR antibodies as potential therapeutic candidates.
Researchers used suPAR-transgenic mice subjected to a high-fat diet plus L-NAME two-hit HFpEF model for 15 weeks to test whether chronically elevated suPAR actively drives disease rather than passively reflecting inflammatory burden. Transgenic animals showed greater diastolic dysfunction, measured by higher E/e' and E/A ratios, and increased pulmonary congestion compared to wild-type controls, while blood pressure and ejection fraction remained unchanged, pointing to a mechanism independent of canonical hemodynamic pathways. Bulk RNA sequencing of left ventricular tissue revealed suppression of mitochondrial oxidative phosphorylation alongside upregulation of innate and adaptive immune programs, including interleukin-1 beta production, leukocyte chemotaxis, and antigen presentation pathways. Spectral flow cytometry showed stepwise expansion of CCR2+ inflammatory monocytes and macrophages in cardiac, splenic, and peripheral blood compartments, corroborated by increased galectin-3+ macrophage density on immunofluorescence. In vitro experiments with bone marrow-derived macrophages demonstrated that recombinant suPAR alone did not trigger inflammation but markedly amplified TNF-alpha, IL-1 beta, IL-6, and NLRP3 responses when cells were subsequently stimulated with LPS and IFN-gamma, establishing a priming mechanism. The authors argue these results identify the CCR2+ monocyte-macrophage axis as the proximate effector of suPAR-driven HFpEF worsening and provide mechanistic rationale for testing anti-suPAR antibodies already in clinical development.
What's missing
As a preprint, this study has not yet undergone peer review. The work is entirely preclinical; it is unknown whether the suPAR-macrophage priming mechanism identified in mice translates to human HFpEF patients. The study does not address whether lowering suPAR after HFpEF is established (rather than preventing elevation) would reverse dysfunction, nor does it characterize the specific receptor through which suPAR primes macrophages. The relevance of the L-NAME plus high-fat diet model to the full heterogeneity of human HFpEF remains a recognized limitation of the field.
What different sources said
- bioRxivCenter
Soluble Urokinase Plasminogen Activator Receptor Primes Macrophages and Worsens Heart Failure with Preserved Ejection Fraction
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