Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain.
Department of Physiology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain.
Cells. 2021 Aug 9;10(8):2035. doi: 10.3390/cells10082035.
Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin receptor (IR) isoforms gene therapy might revert it.
We studied in vivo insulin signaling in aorta artery and heart from iLIRKO. Vascular reactivity and the mRNA levels of genes involved in vascular dysfunction were analyzed in thoracic aorta rings by qRT-PCR. Finally, iLIRKO mice were treated with hepatic-specific gene therapy to analyze vascular dysfunction improvement.
Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues. This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels' imbalance. Finally, regarding long-term hepatic expression of IR isoforms, IRA was more efficient than IRB in the improvement of vascular dysfunction observed in iLIRKO mice.
Severe hepatic insulin resistance is sufficient to produce cardiovascular insulin resistance and dysfunction. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice.
心血管功能障碍与胰岛素抵抗状态有关。在本文中，我们分析了诱导型肝脏特异性胰岛素受体敲除（iLIRKO）的严重肝脏胰岛素抵抗是否会产生血管胰岛素抵抗和功能障碍，以及胰岛素受体（IR）同工型基因治疗是否可以逆转这种情况。
我们研究了 iLIRKO 肝脏和心脏中的体内胰岛素信号。通过 qRT-PCR 分析胸主动脉环中的血管反应性和参与血管功能障碍的基因的 mRNA 水平。最后，用肝特异性基因治疗来分析 iLIRKO 小鼠的血管功能障碍改善情况。
我们的结果表明，严重的肝脏胰岛素抵抗扩展到了心血管组织。从 iLIRKO 小鼠的主动脉中观察到的这种血管胰岛素抵抗与 PI3K/AKT/eNOS 和 p42/44 MAPK 通路的减少相关，并且可能与其血管改变有关，这些改变的特征是内皮功能障碍、高收缩性和 eNOS/iNOS 水平的失衡。最后，关于 IR 同工型的长期肝脏表达，IRA 比 IRB 在改善 iLIRKO 小鼠观察到的血管功能障碍方面更有效。
严重的肝脏胰岛素抵抗足以产生心血管胰岛素抵抗和功能障碍。长期肝脏表达 IRA 恢复了 iLIRKO 小鼠观察到的血管损伤。
