Abstract Body: Heart failure with preserved ejection fraction (HFpEF) is directly linked to systemic inflammation and cardiac dysfunction, representing a leading cause of heart failure. Experimental models support a causal role for immune activation in HFpEF pathogenesis. Despite high prevalence, the molecular mechanisms and potential therapeutic targets responsible for triggering immune cells during HFpEF remain incompletely understood.
Our previous studies identified the spleen as an extramedullary reservoir contributing to monocytic inflammation during experimental cardiometabolic HFpEF. Our data also implicated the bone marrow, the primary site of hematopoiesis. To investigate underlying formative mechanisms of immune mobilization during cardiometablic stress leading to HFpEF, we focused studies on the bone marrow compartment during the acute stages of metabolic and hypertensive stress in experimental mice.
Combined high-fat diet and hypertensive stress promoted early expansion of absolute numbers of inflammatory Ly6cHI monocytes in blood and activation of myeloid progenitor cells within the bone marrow as determined by high resolution flow cytometry. Spatial histologic and confocal immunofluorescence analysis revealed evidence for morphologic remodeling of the bone. This was corroborated by single cell sequencing that detailed transcriptional activation of inflammatory and metabolic signatures in monocyte precursors and bone marrow macrophages. Bioinformatic “Cell Chat” examination predicted new ligand-receptor axes and coordinated interactions between bone macrophages and myeloid progenitors. This was correlated with signatures of mitochondrial activation. Targeted disruption of myeloid mitochondrial metabolism within the bone marrow altered myeloid activation. Cell culture studies corroborated the cell-intrinsic nature of metabolically regulated intercellular-crosstalk.
Together, these findings uncover unique signatures and targets of bone marrow myeloid metabolism and inflammatory signaling during the formative stages of metabolic and hypertensive stress that are the precursor to HFpEF.