{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:14:43Z","timestamp":1785420883007,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,9]]},"group-title":"Immunology","reference-count":34,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["1R01HL153384"],"award-info":[{"award-number":["1R01HL153384"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1R61HL177474"],"award-info":[{"award-number":["1R61HL177474"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Veterans Health Administration","award":["I01CX002684"],"award-info":[{"award-number":["I01CX002684"]}]},{"name":"Veterans Health Administration","award":["1I01CX002560"],"award-info":[{"award-number":["1I01CX002560"]}]},{"id":[{"id":"https:\/\/ror.org\/013kjyp64","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008456","name":"Taubman Medical Research Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008456","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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\u2013derived macrophages with recombinant suPAR before LPS and IFN-\u03b3 stimulation.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Sustained suPAR elevation worsened the established HFpEF phenotype, producing greater diastolic dysfunction (higher E\/e\u2032 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-1\u03b2 production, leukocyte chemotaxis, and antigen presentation. Spectral flow cytometry demonstrated stepwise expansion of CCR2\u207a inflammatory monocytes and macrophages across cardiac, splenic, and peripheral compartments, corroborated in situ by increased galectin-3\u207a macrophage density. In vitro, recombinant suPAR was not a stand-alone inflammatory ligand but instead primed bone marrow\u2013derived macrophages to markedly amplify TNF-\u03b1, IL-1\u03b2, IL-6, and NLRP3 responses to LPS and IFN-\u03b3.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Together, these findings establish that elevated suPAR is sufficient to act as an upstream amplifier of HFpEF, identify the CCR2\u207a 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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.04.730230","type":"posted-content","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T21:05:42Z","timestamp":1781039142000},"source":"Crossref","is-referenced-by-count":0,"title":["Soluble Urokinase Plasminogen Activator Receptor Primes Macrophages and Worsens Heart Failure with Preserved Ejection Fraction"],"prefix":"10.64898","author":[{"given":"Anand Prakash","family":"Singh","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Ann Arbor VA Healthcare System, 2215 Fuller Rd, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parisa","family":"Shabani","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Ann Arbor VA 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