Macrophage 12-lipoxygenase signaling as a therapeutic target in heart failure with preserved ejection fraction - heart failure with preserved ejection fraction (HFPEF) accounts for approximately…

The National Heart, Lung, and Blood Institute awarded the Regents of the University of Michigan $724,971 on August 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate macrophage 12-lipoxygenase signaling as a therapeutic target in heart failure with preserved ejection fraction (HFPEF).

The research program establishes 12-lipoxygenase (12-LOX), an enzyme that converts arachidonic acid into bioactive lipid mediators, as a master regulator of HFPEF progression by controlling macrophage inflammatory responses. The work combines macrophage-specific genetic deletion models with lipidomic profiling and immune phenotyping to determine the role of 12-LOX in macrophage polarization-mediated pathogenesis of HFPEF, identify molecular mechanisms by which 12-LOX-mediated macrophage polarization influences disease progression, and examine the therapeutic potential of novel 12-LOX inhibitors in attenuating HFPEF. Preliminary studies demonstrate that mice lacking 12-LOX or treated with systemic 12-LOX inhibition show markedly reduced cardiac dysfunction and inflammation when subjected to metabolic stress that typically induces HFPEF.

Performance occurs in Ann Arbor, Michigan. The award period runs from August 1, 2026, through April 30, 2030. This is a Project Grant, the standard assistance type for investigator-initiated research under NHLBI's portfolio.

Macrophage 12-lipoxygenase signaling as a therapeutic target in heart failure with preserved ejection fraction - heart failure with preserved ejection fraction (HFPEF) accounts for approximately half of all heart failure cases. Yet, we lack effective therapies because traditional approaches fail to address the underlying inflammatory pathophysiology chronic inflammation, driven by dysregulated macrophage activation, emerges as a central mechanism amenable to therapeutic intervention. We propose that 12-lipoxygenase (12-LOX), an enzyme that converts arachidonic acid into bioactive lipid mediators, serves as a master regulator of HFPEF progression by controlling macrophage inflammatory responses. Our preliminary studies reveal compelling evidence: mice lacking 12-LOX or treated with systemic 12-LOX inhibition show markedly reduced cardiac dysfunction and inflammation when subjected to metabolic stress that typically induces HFPEF. However, critical questions remain unanswered about how macrophagespecific 12-LOX activity drives disease progression and whether pharmacological targeting offers therapeutic benefit our research program aims to transform HFPEF treatment by establishing 12-LOX as a druqgable target that reprograms pathological macrophage activation. Through an integrated approach combining macrophage-specific genetic deletion models with comprehensive lipidomic profiling and immune phenotyping, we will address three fundamental questions: 1) determine the role of 12-LOX in macrophage polarization-mediated pathogenesis of hfpe; 2) identify the molecular mechanisms by which 12-LOX-mediated macrophage polarization influences HFPEF progression; 3) examine the therapeutic potential of novel 12- LOX inhibitors in attenuating HFPEF. This work will establish the mechanistic foundation linking lipid metabolism to immune dysfunction in HFPEF while validating therapeutic strategies poised for clinical translation. By targeting the upstream enzymatic driver rather than downstream inflammatory mediators, our approach addresses the root cause of pathological inflammation. The availability of our compounds, already in human trials, accelerates the path from bench to bedside, offering the potential to deliver the first mechanism-based therapy for a condition affecting millions of patients worldwide.