N-cadherin coordinates AMP kinase-mediated lung vascular repair

作者：Jian Ming Yuan; Liu Yanping; Li Qian; Wolkowicz Paul; Alexeyev Mikhail; Zmijewski Jaroslaw; Creighton Judy^*

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2016, 310(1): L71-L85.

DOI：10.1152/ajplung.00227.2015

• permeability
• edema
• endothelium
• pulmonary
• adhesion

Injury to the pulmonary circulation compromises endothelial barrier function and increases lung edema. Resolution of lung damage involves restoring barrier integrity, a process requiring reestablishment of endothelial cell-cell adhesions. However, mechanisms underlying repair in lung endothelium are poorly understood. In pulmonary microvascular endothelium, AMP kinase alpha 1 (AMPK alpha 1) stimulation enhances recovery of the endothelial barrier after LPS-induced vascular damage. AMPK alpha 1 colocalizes to a discrete membrane compartment with the adhesion protein neuronal cadherin (N-cadherin). This study sought to determine N-cadherin's role in the repair process. Short-hairpin RNA against full-length N-cadherin or a C-terminally truncated N-cadherin, designed to disrupt the cadherin's interactions with intracellular proteins, were expressed in lung endothelium. Disruption of N-cadherin's intracellular domain caused translocation of AMPK away from the membrane and attenuated AMPK-mediated restoration of barrier function in LPS-treated endothelium. AMPK activity measurements indicated that lower basal AMPK activity in cells expressing the truncated N-cadherin compared with controls. Moreover, the AMPK stimulator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) failed to increase AMPK activity in cells expressing the modified N-cadherin, indicating uncoupling of a functional association between AMPK and the cadherin. Isolated lung studies confirmed a physiologic role for this pathway in vivo. AMPK activation reversed LPSinduced increase in permeability, whereas N-cadherin inhibition hindered AMPK-mediated repair. Thus N-cadherin coordinates the vascular protective actions of AMPK through a functional link with the kinase. This study provides insight into intrinsic repair mechanisms in the lung and supports AMPK stimulation as a modality for treating vascular disease.

• 出版日期2016-1-1