Sustained suPAR elevation worsened the established HFpEF phenotype in mice, producing greater diastolic dysfunction and pulmonary congestion by priming macrophages to amplify inflammatory responses.
Does elevated suPAR worsen the HFpEF phenotype in a cardiometabolic mouse model?
Elevated suPAR acts as an upstream amplifier of HFpEF by priming macrophages, worsening diastolic dysfunction and pulmonary congestion in a preclinical model.
Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a systemic inflammatory syndrome with few effective therapies. Soluble urokinase plasminogen activator receptor (suPAR), a circulating immune-derived glycoprotein, independently predicts adverse outcomes in HFpEF beyond natriuretic peptides, but whether it is a causal driver or a passive marker of inflammatory burden has remained unresolved. Methods We tested the hypothesis that elevated circulating suPAR is sufficient to amplify HFpEF by acting on the innate immune system. suPAR-transgenic (suPAR-Tg) and wild-type mice were subjected to a cardiometabolic two-hit model (high-fat diet plus L-NAME) for 15 weeks. Cardiac structure and diastolic function were assessed by serial echocardiography alongside blood pressure, glucose tolerance, and gravimetric endpoints, and left ventricular tissue was profiled by bulk RNA sequencing with in silico cellular deconvolution. Myeloid populations in the heart, spleen, and peripheral blood were quantified by spectral flow cytometry and corroborated by galectin-3 immunofluorescence, and the direct effect of suPAR on macrophages was tested by priming bone marrow–derived macrophages with recombinant suPAR before LPS and IFN-γ stimulation. Results Sustained suPAR elevation worsened the established HFpEF phenotype, producing greater diastolic dysfunction (higher E/e′ and E/A ratios) and pulmonary congestion without altering blood pressure or ejection fraction, indicating a mechanism downstream of the canonical hemodynamic stimulus. Bulk RNA sequencing of left ventricular tissue revealed a coordinated transcriptional shift, with suppression of mitochondrial oxidative phosphorylation and amplification of innate and adaptive immune programs, including interleukin-1β production, leukocyte chemotaxis, and antigen presentation. Spectral flow cytometry demonstrated stepwise expansion of CCR2⁺ inflammatory monocytes and macrophages across cardiac, splenic, and peripheral compartments, corroborated in situ by increased galectin-3⁺ macrophage density. In vitro, recombinant suPAR was not a stand-alone inflammatory ligand but instead primed bone marrow–derived macrophages to markedly amplify TNF-α, IL-1β, IL-6, and NLRP3 responses to LPS and IFN-γ. Conclusions Together, these findings establish that elevated suPAR is sufficient to act as an upstream amplifier of HFpEF, identify the CCR2⁺ inflammatory monocyte-macrophage axis as its proximate effector, and convert two decades of epidemiologic association into a mechanistically grounded, therapeutically tractable hypothesis with immediate relevance to clinical-stage anti-suPAR antibodies.
Singh et al. (Tue,) conducted a other in Heart failure with preserved ejection fraction (HFpEF). Elevated circulating suPAR (suPAR-transgenic model) vs. Wild-type mice was evaluated on Cardiac structure, diastolic function, and myeloid populations. Sustained suPAR elevation worsened the established HFpEF phenotype in mice, producing greater diastolic dysfunction and pulmonary congestion by priming macrophages to amplify inflammatory responses.