Sunday, May 18, 2025
5/18/2025
Novel pathogenesis of LVNC - PROJECT SUMMARY Left ventricular noncompaction cardiomyopathy (LVNC) is a rare morphological abnormality of the myocardium occurred during early heart development characterized by excessive trabeculae with deep inter- trabecular recesses, but thin free wall. LVNC is classified as the third most common cardiomyopathy, with a prognosis ranging from asymptotic to preterm death, cardiac arrythmia, and heart failure. Recent advances in imaging technology have led to increased detection of LVNC, although the underlying cellular and molecular causes remain elusive. Previous studies have mainly focused on intrinsic defects in myocardium, yet mounting evidence also suggests that LVNC is associated with impaired function of non-muscle cell types in the developing heart including cardiac endothelial cells (CECs), which are highly heterogenous, composed of both endocardial and coronary endothelial cells. Previous studies have shown that both endocardial endothelial cells (EECs) and coronary endothelial cells (CoECs) are required for proper trabecular and compact myocardial morphogenesis, although the underlying cellular and molecular mechanisms remain elusive. We discovered that global knockout (KO) of Zip8, a zinc ion importer, results in LVNC and preterm lethality in mice, suggesting that Zip8 plays indispensable roles during myocardial trabeculation and compaction. However, it is unclear through what cellular and molecular mechanisms Zip8 impacts myocardial formation. Using various Cre driver mouse lines, our preliminary data demonstrated that only endothelial deletion of Zip8 recapitulated the LNVC phenotype seen in global Zip8 KO hearts. Surprisingly, the proportions of EECs and CoECs in Zip8 endothelial KO (Zip8eko) hearts were skewed; compared to control littermates, EECs were significantly more abundant, whereas CoECs were less abundant in Zip8eko hearts. We also found that certain paracrine growth factors such as Insulin-like growth factor 2 (IGF2) were significantly upregulated in Zip8eko hearts, which is consistent with an increased EEC population, and may contribute to the hypertrabecuation phenotype. Conversely, we also found that coronary vessels were significant fewer in Zip8eko hearts, accompanied by decreased VEGF signaling, a major angiogenic pathway during early heart formation. These results are consistent with a reduced CoEC population, which together account for the noncompaction phenotype. Accordingly, we hypothesize that Zip8/Zn in CECs orchestrates myocardial morphogenesis by determining endothelial cell identity and modulating trabecular growth and coronary angiogenic signaling. We will test this hypothesis using multiple genetic and biochemical approaches. Upon completion of this study, we will gain novel insights on the pathogenesis of LVNC.
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