SCUBE3 promotes angiogenesis after myocardial infarction by stimulating endothelial fatty acid metabolism

ABSTRACT: BACKGROUND: Myocardial infarction (MI), a leading cause of death globally, continues to pose significant clinical challenges due to the constraints of existing treatment options. The cardiac vascular system, which forms the essential framework supporting myocardial function, delivers oxygen and nutrients with precise regulation to heart tissue. Nevertheless, the complex regulatory processes controlling this network after MI remain not fully understood. Importantly, the central involvement of cardiac endothelial cells in the pathophysiological development of MI necessitates more in-depth investigation. METHODS: We investigated changes in the expression of Signal Peptide, CUB Domain And EGF Like Domain Containing 3 (SCUBE3) protein in the myocardium from MI-affected mice and human MI cardiac tissues. Using genetically modified mouse models alongside various cellular and molecular biology methods, we thoroughly explored the functional role of SCUBE3 in MI and its mechanisms related to cardiac endothelial cell metabolism. RESULTS: Proteomic analysis of serum from MI patients revealed a significant increase in SCUBE3 protein levels. Immunohistochemical studies showed a pronounced elevation of SCUBE3 predominantly localized in fibroblasts within the infarcted regions of cardiac tissues from MI patients. Similarly, in a mouse MI model, SCUBE3 expression was upregulated and mainly found in fibroblasts in the damaged myocardial areas. Through inducible, fibroblast-specific SCUBE3 overexpression and knockout mouse models, we found that SCUBE3 overexpression significantly promoted angiogenesis after MI, enhanced microvascular network integrity, and mitigated myocardial damage. Conversely, deletion of SCUBE3 worsened cardiac injury following infarction. Subsequent protein interaction assays and mass spectrometry identified that SCUBE3 specifically binds to and activates vascular endothelial growth factor receptor 1 (VEGFR1) on endothelial cells, triggering downstream signaling pathways. Transcriptomic analysis demonstrated that SCUBE3 substantially upregulates pathways related to fatty acid metabolism. Live-cell dynamic studies confirmed that SCUBE3 facilitates fatty acid uptake and increases metabolic activity in endothelial cells. Metabolomic profiling further indicated that SCUBE3 aids in converting unsaturated fatty acids into phosphosugars and nucleotides, providing critical substrates and energy to support endothelial proliferation. In SCUBE3-overexpressing mice, endothelial cell–specific inducible deletion of VEGFR1 completely abolished SCUBE3-induced fatty acid metabolism and its cardioprotective benefits. Additionally, beyond its angiogenic function, SCUBE3 notably improves cardiomyocyte regenerative ability, underscoring its potential as a novel therapeutic target for myocardial repair.

ORGANISM(S): Homo Sapiens

SUBMITTER: Weitao Cong  

PROVIDER: PXD068476 | iProX | Thu Sep 18 00:00:00 BST 2025

REPOSITORIES: iProX