Background and Purpose:Although reperfusion therapy and modern drug treatments have significantly improved post-myocardial infarction (MI) survival, many patients still develop heart failure after MI. Short-term inhibition of ADAM10, a membrane-anchored protease that becomes upregulated in cardiomyocytes after MI, has recently been identified as a promising therapeutic strategy to preserve cardiac function and reduce scar size via diminished neutrophil infiltration and permanent reduction of systemic and cardiac IL-1β levels. IL-1β plays a central role in the formation of the metabolic and epigenetic changes that drive biased myelopoiesis, a process that could contribute to chronic low-grade cardiac inflammation and thus heart failure progression after MI. However, whether MI induces myeloid bias remains to be determined. Here, we identify a cardiomyocyte-to-bone-marrow communication axis that metabolically and epigenetically reprograms hematopoietic Linage (Lin)⁻ progenitor cells after MI.
Methods and Results:Lin- hematopoietic stem and progenitor cells (HSPCs) were harvested from cardiomyocyte-specific Adam10 knockout and wildtype mice 28 days after infarct or sham surgery. Both metabolomic profiling and single-cell ATAC-seq (scATAC-seq) were performed. MI induced long-lasting metabolic reprogramming of Lin⁻ progenitor cells. At 28 days post-MI, Lin- cells accumulated succinate and fumarate, metabolites known to stabilize HIF1α and inhibit α-ketoglutarate-dependent dioxygenases, thereby promoting sustained epigenetic remodeling. Strikingly, in cardiomyocyte-specific Adam10 knockout mice, MI does not trigger a post-ischemic rise in succinate and fumarate in Lin⁻ cells; metabolite levels remain comparable to sham controls and are markedly reduced relative to Adam10 wildtype mice. Consequently, CD11b⁺ myeloid cells isolated 28 days post-MI displayed a less inflammatory phenotype, with blunted responses to secondary LPS stimulation. These changes coincided with persistently elevated circulating neutrophil and monocyte counts. Flow cytometry also revealed increased T helper cell expansion in the spleen of ADAM10 knockout mice, suggesting a role for ADAM10 in regulating adaptive immunity after MI.
Conclusion:Together, our data reveal a mechanism by which injured cardiomyocytes shape systemic immunity long after MI. By linking myocardial ADAM10 activity to persistent metabolic changes in hematopoietic progenitors and elevated inflammatory responsiveness of myeloid cells, this work identifies a tractable node for therapeutic intervention. Targeted disruption of this pathway may limit chronic post-ischemic inflammation and help decelerate the transition from MI to heart failure.
