Cysteine-rich with EGF-like domains 2 (CRELD2) is an endoplasmic reticulum stress-inducible angiogenic growth factor promoting ischemic heart repair.
Xuekun WuLinqun ZhengMarc R RebollLillian F HydeElvira MassHans W NiessenMaike KosankeAndreas PichEvangelos GiannitsisJochen TillmannsJohann BauersachsJoerg HeinekeYong WangMortimer Korf-KlingebielFelix PoltenKai C WollertPublished in: Nature cardiovascular research (2024)
Tissue repair after myocardial infarction (MI) is guided by autocrine and paracrine-acting proteins. Deciphering these signals and their upstream triggers is essential when considering infarct healing as a therapeutic target. Here we perform a bioinformatic secretome analysis in mouse cardiac endothelial cells and identify cysteine-rich with EGF-like domains 2 (CRELD2), an endoplasmic reticulum stress-inducible protein with poorly characterized function. CRELD2 was abundantly expressed and secreted in the heart after MI in mice and patients. Creld2-deficient mice and wild-type mice treated with a CRELD2-neutralizing antibody showed impaired de novo microvessel formation in the infarct border zone and developed severe postinfarction heart failure. CRELD2 protein therapy, conversely, improved heart function after MI. Exposing human coronary artery endothelial cells to recombinant CRELD2 induced angiogenesis, associated with a distinct phosphoproteome signature. These findings identify CRELD2 as an angiogenic growth factor and unravel a link between endoplasmic reticulum stress and ischemic tissue repair.
Keyphrases
- endoplasmic reticulum stress
- growth factor
- endothelial cells
- induced apoptosis
- heart failure
- high glucose
- wild type
- coronary artery
- end stage renal disease
- atrial fibrillation
- left ventricular
- newly diagnosed
- chronic kidney disease
- acute myocardial infarction
- vascular endothelial growth factor
- ejection fraction
- stem cells
- pulmonary artery
- drug induced
- prognostic factors
- adipose tissue
- mesenchymal stem cells
- metabolic syndrome
- type diabetes
- early onset
- protein protein
- amino acid
- skeletal muscle
- signaling pathway
- smoking cessation
- percutaneous coronary intervention
- subarachnoid hemorrhage
- diabetic rats
- data analysis
- brain injury
- pulmonary arterial hypertension
- acute heart failure