Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, The University of Toledo, Toledo, OH 43614, USA.
Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences, The University of Toledo, Toledo, OH 43614, USA; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA.
Mol Metab. 2018 Mar;9:98-113. doi: 10.1016/j.molmet.2018.01.009. Epub 2018 Jan 31.
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 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 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 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 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 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.
CC1 基因敲除的小鼠表现出胰岛素清除受损，导致高胰岛素血症，进而出现胰岛素抵抗、肝内从头脂肪生成增加和内脏肥胖。此外，它们还表现出血管通透性异常和血压升高。肝特异性恢复 CEACAM1 可逆转 CC1 小鼠的所有代谢异常。本研究探讨了 CC1 雄性小鼠是否会出现内皮和心脏功能障碍，以及这是否与胰岛素提取缺陷引起的代谢异常有关。
血管张力研究显示，CC1 小鼠阻力小动脉中激动剂刺激的一氧化氮产生减少，但 CC1 小鼠没有。基于肝的 CEACAM1 恢复也减轻了循环白细胞与内皮细胞异常黏附，同时降低了血浆内皮素-1 并恢复了血浆一氧化氮水平。超声心动图研究显示，CC1 小鼠室间隔壁增厚、心脏肥大和心功能降低，但 CC1 小鼠没有。胰岛素信号转导实验表明，IRS1/Akt/eNOS 通路受损导致一氧化氮水平降低，Shc/MAPK 通路激活导致主动脉和心脏中内皮素-1 生成增加，而 CC1 小鼠没有。内皮素-1 受体 A/B 比值增加表明 CC1 小鼠的血管舒缩活性失衡，而 CC1 小鼠的这种失衡得到了纠正。
数据强调了受损的 CEACAM1 依赖性肝胰岛素清除途径以及由此导致的高胰岛素血症和脂质在主动脉和心脏中的积累在调节心血管功能中的关键作用。
