Liver-specific rescuing of CEACAM1 reverses endothelial and cardiovascular abnormalities in male mice with null deletion of Ceacam1 gene

• Published in: Molecular metabolism (Germany) 2018-03, Vol.9, p.98-113
• Main Authors: Russo, Lucia, Muturi, Harrison T., Ghadieh, Hilda E., Wisniewski, Alexander M., Morgan, Eric E., Quadri, Syed S., Landesberg, Gavin P., Siragy, Helmy M., Vazquez, Guillermo, Scalia, Rosario, Gupta, Rajesh, Najjar, Sonia M.
• Format: Article
• Language: English
• Subjects: Animals; Carcinoembryonic Antigen - genetics; Carcinoembryonic Antigen - metabolism; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathy; Cells, Cultured; Endothelial function; Endothelins - metabolism; Endothelium, Vascular - metabolism; Gene Deletion; Hyperinsulinemia; Hyperinsulinism - genetics; Hyperinsulinism - metabolism; Insulin clearance; Insulin Receptor Substrate Proteins - metabolism; Insulin Resistance; Liver - metabolism; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Myocytes, Cardiac - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Original; Proto-Oncogene Proteins c-akt - metabolism
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2018.01.009

Mice with global null mutation of Ceacam1 (Cc1−/−), display impairment of insulin clearance that causes hyperinsulinemia followed by insulin resistance, elevated hepatic de novo lipogenesis, and visceral obesity. In addition, they manifest abnormal vascular permeability and elevated blood pressure. Liver-specific rescuing of Ceacam1 reversed all of the metabolic abnormalities in Cc1−/−liver+ mice. The current study examined whether Cc1−/− male mice develop endothelial and cardiac dysfunction and whether this relates to the metabolic abnormalities caused by defective insulin extraction. Myography studies showed reduction of agonist-stimulated nitric oxide production in resistance arterioles in Cc1−/−, but not Cc1−/−liver+ mice. Liver-based rescuing of CEACAM1 also attenuated the abnormal endothelial adhesiveness to circulating leukocytes in parallel to reducing plasma endothelin-1 and recovering plasma nitric oxide levels. Echocardiography studies revealed increased septal wall thickness, cardiac hypertrophy and reduced cardiac performance in Cc1−/−, but not Cc1−/−xliver+ mice. Insulin signaling experiments indicated compromised IRS1/Akt/eNOS pathway leading to lower nitric oxide level, and activated Shc/MAPK pathway leading to more endothelin-1 production in the aortae and hearts of Cc1−/−, but not Cc1−/−xliver+ mice. The increase in the ratio of endothelin-1 receptor A/B indicated an imbalance in the vasomotor activity of Cc1−/− mice, which was normalized in Cc1−/−xliver+ mice. The data underscore a critical role for impaired CEACAM1-dependent hepatic insulin clearance pathways and resulting hyperinsulinemia and lipid accumulation in aortae and heart in regulating the cardiovascular function. •Mice with global deletion of Ceacam1 gene (Cc1−/−) manifest endothelial dysfunction which is reversed by liver-specific rescuing of CEACAM1.•Restoring CEACAM1 expression in the liver reversed cardiac hypertrophy and rescued cardiac performance.•Hyperinsulinemia emerging from impaired insulin clearance regulates endothelial and cardiovascular functions.