Loss of CEACAM1 in Endothelial Cells Contributes to the Development of Cardiac Fibrosis

Abstract

Carcinoembryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1) has been implicated in various physiological processes in the vascular systems, including blood vessel formation, and endothelial barrier function. Consistent with a role for hepatic CEACAM1 in promoting insulin sensitivity by mediating insulin clearance and maintaining physiologic plasma insulin levels, we have recently identified a role for hepatic CEACAM1 in preventing cardiac hypertrophy and dysfunction. The aim of this study was to elucidate the contribution of endothelial cell CEACAM1 in cardiac function and fibrosis that has remained elusive. To this end, we generated an endothelial cell-specific Ceacam1 knockout mouse line (VECadCc1−/−). Gomori Trichrome Blue Staining revealed a significant perivascular and interstitial fibrosis in the heart of VECadCc1−/− mice compared to their control littermates. Consistently, the mRNA levels of markers of fibrosis [collagen 1A1, α-SMA and fibroblast-specific protein1 (FSP1)] were elevated with a reciprocal decrease of endothelial cell makers (CD31), indicating endothelial mesenchymal transition (EndMT) in these mice. Cardiac fibrosis was associated with increased activation of the TGF-β1-Smad2/3 signaling pathway. Immunofluorescence staining co-localized CD31 with α-SMA in the myocardial perivascular section of VECadCc1−/− hearts. Moreover, mRNA level of α-SMA, FSP1, SNAIL and SLUG were up-regulated while that of CD31 was down-regulated in mouse heart endothelial cells (MHEC) isolated from VECadCc1−/− mice. The Akt/eNOS pathway was basally inactivated, leading to lower nitric oxide (NO) level in MHEC isolated from VECadCc1−/− mice. Moreover, loss of endothelial CEACAM1 caused reduced association with SHP-2 phosphatase and consequently, reduction in insulin-stimulated IRS-1/Akt/eNOS activation.These studies identified an important role for the loss of CEACAM1 in endothelial cells as a mechanism underlying cardiac fibrosis. Disclosure H.T. Muturi: None. H.E. Ghadieh: None. S.S. Khuder: None. S. Jash: None. R. Abu Helal: None. N.A. Daniels: None. J. Liu: None. V. Puri: None. G. Vazquez: None. R. Gupta: None. S.M. Najjar: None.