PXD068507

PXD068507 is an original dataset announced via ProteomeXchange.

Title	SCUBE3 enhances post-myocardial infarction angiogenesis by promoting endothelial fatty acid metabolism
Description	BACKGROUND: Myocardial infarction (MI), one of the leading causes of mortality worldwide, remains a clinical challenge due to limitations in current therapeutic strategies. The cardiac vascular network, as the fundamental architecture sustaining myocardial function, delivers oxygen and nutrients with high precision to the heart tissue. However, the dynamic regulatory mechanisms governing this network post-MI remain incompletely elucidated. Notably, the pivotal role of cardiac endothelial cells in the pathophysiological progression of MI calls for further comprehensive investigation. METHODS: We examined alterations in Signal Peptide, CUB Domain And EGF Like Domain Containing 3 (SCUBE3) protein expression in the myocardium of MI-afflicted mice and human MI heart tissues. Utilizing genetically engineered mouse models in combination with diverse cellular and molecular biology techniques, we systematically dissected the functional role of SCUBE3 in MI and its underlying mechanisms in cardiac endothelial cell metabolism. RESULTS: Proteomic profiling of serum samples from MI patients demonstrated a significant elevation in SCUBE3 protein levels. Immunohistochemical assessment revealed markedly increased SCUBE3 expression localized predominantly within fibroblasts in the infarct zone of cardiac tissues from MI patients. Consistently, in a murine MI model, SCUBE3 expression was also upregulated and primarily distributed in fibroblasts within the infarcted myocardial regions. Employing inducible, fibroblast-specific SCUBE3 overexpression and knockout mouse models, we observed that SCUBE3 overexpression robustly enhanced post-MI angiogenesis, improved microcirculatory network integrity, and attenuated myocardial injury. In contrast, SCUBE3 ablation exacerbated infarct-induced cardiac damage. Subsequent protein tracking and mass spectrometry analyses demonstrated that SCUBE3 selectively binds to and activates vascular endothelial growth factor receptor 1 (VEGFR1) on endothelial cells, thereby mediating downstream biological effects. Transcriptomic sequencing revealed that SCUBE3 significantly upregulates fatty acid metabolism–related pathways. Live-cell dynamic analysis further confirmed that SCUBE3 promotes fatty acid uptake and enhances the metabolic activity of endothelial cells. Metabolomic profiling indicated that SCUBE3 facilitates the conversion of unsaturated fatty acids into phosphosugars and nucleotides, supplying essential substrates and energy to support endothelial cell proliferation. In SCUBE3-overexpressing mice, endothelial cell–specific inducible VEGFR1 knockout completely abrogated SCUBE3-driven fatty acid metabolism and its associated cardioprotective effects. Moreover, beyond its role in angiogenesis SCUBE3 also markedly enhances cardiomyocyte regenerative capacity, highlighting its potential as a novel therapeutic target for myocardial repair. Conclusions: Our findings establish that fibroblast-derived SCUBE3 interacts with VEGFR1 on endothelial cells to promote fatty acid metabolism, thereby providing energy substrates necessary for endothelial proliferation. This study elucidates the critical function of the SCUBE3–VEGFR1 signaling axis in post-MI vascular regeneration through metabolic regulation, presenting a promising avenue for therapeutic intervention in cardiac repair.
HostingRepository	iProX
AnnounceDate	2025-09-17
AnnouncementXML	Submission_2025-09-18_18:42:06.879.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Zhicheng Hu
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 240

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-18 18:39:47	ID requested
⏵ 1	2025-09-18 18:42:07	announced

Dataset with its publication pending

submitter keyword: Fatty Acid Metabolism, Endothelial Cells, Myocardial Infarction, Angiogenesis, SCUBE3, VEGFR1

Weitao Cong
contact affiliation	School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, P.R. China
contact email	cwt97126@126.com
lab head
Zhicheng Hu
contact affiliation	School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, P.R. China
contact email	huzhicheng9712@163.com
dataset submitter

iProX dataset URI