Abstract Thu064: Lack of cardiac endothelial Zip8 leads to left ventricular noncompaction cardiomyopathy

Failure of proper embryonic myocardial trabeculation and compaction leads to left ventricular noncompaction cardiomyopathy (LVNC). Cardiac endothelial cells (CECs) play critical roles in supporting proper myocardial trabeculation and compaction. For instance, reduction of coronary angiogenesis in mice leads to LVNC. Previously, our group showed that global knockout (KO) of Zip8, a zinc importer, resulted in LVNC in mice, but the underlying cellular and molecular mechanisms await further investigation. Using various Cre driver mice, we found that only endothelial deletion of Zip8 recapitulated the LNVC phenotypes present in Zip8 global KO hearts. Intriguingly, we found that the proportions of endocardial endothelial cells (EECs) and coronary endothelial cells (CoECs) in Zip8 endothelial KO ( Zip8 eko ) hearts were skewed: there were significantly more EECs but significantly fewer CoECs in Zip8 eko hearts as compared to littermate controls. The number of coronary vessels was significantly reduced in Zip8 eko hearts as compared to controls, along with decreased expression of vascular endothelial growth factor receptor 2 (VEGFR2), a critical angiogenic factor. Further, the angiogenic defect was recapitulated in cultured Zip8 KO mouse CECs (MCECs), and this phenotype was successfully rescued by Vegfr2 overexpression. The transcriptional activity of Metal regulatory transcriptional factor 1 (MTF1) is subject to the regulation by ZIP8. Interestingly, we found that Mtf1 knockdown also resulted in angiogenetic defects in cultured MCECs along with VEGFR2 reduction. Finally, we found that MTF1 directly regulates Vegfr2 transcription. In conclusion, our findings illustrate that Zip8 in CECs regulates myocardial morphogenesis through the MTF1-VEGFR2 axis, providing new insights into the pathogenesis of LVNC.