Pengfei Lu

Background: Acute and chronic heart failure secondary to myocardial infarction (MI) and cardiac ischemia–reperfusion injury (IRI) are leading causes of death in ischemic heart disease. A mouse model is indispensable for investigating MI and IRI, and the development of reliable mouse MI and IRI models is essential for advancing research in this field. The clear early diagnostic criteria for confirming successful induction of MI and IRI in mice remain lacking. Methods: Adult C57BL/6J background mice underwent left anterior descending coronary artery ligation to induce acute MI, or ligation followed by reperfusion to induce IRI. The success of the MI and IRI model establishment was confirmed by 2,3,5‐triphenyltetrazolium chloride staining and echocardiography. Electrocardiography was used to monitor the electric activity in the mice. Conclusions: Electrocardiography demonstrated that ST‐segment elevation in ECG lead II and corrected QTc interval prolongation at 30 minutes following left anterior descending ligation as 2 key early indicators of successful MI. Echocardiography analysis revealed that the magnitude of ST‐segment elevation strongly correlated with the left anterior descending ligation site, where a more proximal ligation produced a greater ST‐segment elevation amplitude and more severe ischemia. In IRI models, ST‐segment elevation typically resolved and returned to baseline within 20 minutes of reperfusion. This study developed quantifiable early diagnostic criteria for successful MI and IRI induction based on characteristic ECG changes. These quantifiable ECG parameters provide early diagnostic standards that can significantly streamline and optimize modeling procedures.

Background: Endocardial cells are a major progenitor population that gives rise to heart valves through endocardial cushion formation by endocardial to mesenchymal transformation and the subsequent endocardial cushion remodeling. Genetic variants that affect these developmental processes can lead to congenital heart valve defects. Crk and Crkl are ubiquitously expressed genes encoding cytoplasmic adaptors essential for cell signaling. This study aims to explore the specific role of Crk and Crkl in the endocardial lineage during heart valve development. Methods and Results: We deleted Crk and Crkl specifically in the endocardial lineage. The resultant heart valve morphology was evaluated by histological analysis, and the underlying cellular and molecular mechanisms were investigated by immunostaining and quantitative reverse transcription polymerase chain reaction. We found that the targeted deletion of Crk and Crkl impeded the remodeling of endocardial cushions at the atrioventricular canal into the atrioventricular valves. We showed that apoptosis was temporally increased in the remodeling atrioventricular endocardial cushions, and this developmentally upregulated apoptosis was repressed by deletion of Crk and Crkl . Loss of Crk and Crkl also resulted in altered extracellular matrix production and organization in the remodeling atrioventricular endocardial cushions. These morphogenic defects were associated with altered expression of genes in BMP (bone morphogenetic protein), connective tissue growth factor, and WNT signaling pathways, and reduced extracellular signal‐regulated kinase signaling activities. Conclusions: Our findings support that Crk and Crkl have shared functions in the endocardial lineage that critically regulate atrioventricular valve development; together, they likely coordinate the morphogenic signals involved in the remodeling of the atrioventricular endocardial cushions.

Developmental etiologies causing complex congenital aortic root abnormalities are unknown. Here we show that deletion ofSox17in aortic root endothelium in mice causes underdeveloped aortic root leading to a bicuspid aortic valve due to the absence of non-coronary leaflet and mispositioned left coronary ostium. The respective defects are associated with reduced proliferation of non-coronary leaflet mesenchyme and aortic root smooth muscle derived from the second heart field cardiomyocytes. Mechanistically, SOX17 occupies aPdgfbtranscriptional enhancer to promote its transcription andSox17deletion inhibits the endothelialPdgfbtranscription and PDGFB growth signaling to the non-coronary leaflet mesenchyme. Restoration of PDGFB in aortic root endothelium rescues the non-coronary leaflet and left coronary ostium defects inSox17nulls. These data support a SOX17-PDGFB axis underlying aortic root development that is critical for aortic valve and coronary ostium patterning, thereby informing a potential shared disease mechanism for concurrent anomalous aortic valve and coronary arteries.

New coronary vessels are added to the heart around birth to support postnatal cardiac growth. Here we show that, in late fetal development, the embryonic coronary plexus at the inner myocardium of the ventricles expresses the angiogenic signalling factors VEGFR3 and DLL4 and generates new coronary vessels in neonates. Contrary to a previous model in which the formation of new coronary vessels in neonates from ventricular endocardial cells was proposed, we find that late fetal and neonatal ventricular endocardial cells lack angiogenic potential and do not contribute to new coronary vessels. Instead, we show using lineage-tracing as well as gain- and loss-of-function experiments that the pre-existing embryonic coronary plexus at the inner myocardium undergoes angiogenic expansion through the DLL4–NOTCH1 signalling pathway to vascularize the expanding myocardium. We also show that the pre-existing coronary plexus revascularizes the regenerating neonatal heart through a similar mechanism. These findings provide a different model of neonatal coronary angiogenesis and regeneration, potentially informing cardiovascular medicine.