Extracellular BRICK1 drives heart repair after myocardial infarction
Tissue repair after myocardial infarction entails a vigorous angiogenic response that mitigates scarring and worsening of heart function and may represent a therapeutic target. Angiogenesis in the infarct wound is guided by incompletely defined myeloid cell–endothelial cell interactions. Here we identify the myeloid cell-expressed 75-amino acid microprotein BRICK1 (short name: BRK1) as an indispensable driver of postinfarction angiogenesis. As a subunit of the intracellular actin-regulatory WAVE complex, BRK1 was not previously known to function outside the cell. We show that BRK1 translocates to the extracellular space after myocardial infarction in mice and humans. We find that BRK1 is not actively secreted but released from dying monocytes and macrophages. Cre-loxP-mediated myeloid cell-selective genetic deletion of Brk1 or antibody neutralization of extracellular BRK1 impaired microvessel formation in the infarct border zone and resulted in severe postinfarction heart failure in mice. Treatment with recombinant BRK1, conversely, preserved heart function after myocardial infarction. Mechanistically, BRK1 induced an angiogenic phenotype in human cardiac endothelial cells by signaling via the small GTPase RAP1 and mitogen-activated protein kinases 1 and 3 to promote retinoblastoma protein hyperphosphorylation and E2F transcription factor activation. BRK1 thus emerges as an angiogenic growth factor linking myeloid cell death to ischemic tissue repair and potentially enabling a protein-based therapy for myocardial infarction. Overall design: Bulk-RNA sequencing of human coronary artery endothelial cells cultured for 8 hours in the absence (control) or presence of BRK1, VEGFA, PD98059, or PD plus BRK1.