Journal article

Publication year: 2010

Pages: 1237-U363

Journal: Arteriosclerosis, Thrombosis, and Vascular Biology

Volume number: 30

Issue number: 6

ISSN: 1079-5642

eISSN: 1524-4636

Open access status: Bronze

DOI Link: https://doi.org/10.1161/ATVBAHA.110.203901

Publisher: American Heart Association

Abstract: 

Objective-Insulin is a key regulator of metabolism, but it also confers protective effects on the cardiovascular system. Here, we analyze the mechanism by which insulin stabilizes endothelial barrier function.

Methods and Results-Insulin reduced basal and antagonized tumor necrosis factor-alpha-induced macromolecule permeability of rat coronary microvascular endothelial monolayers. It also abolished reperfusion-induced vascular leakage in isolated-perfused rat hearts. Insulin induced dephosphorylation of the regulatory myosin light chains, as well as translocation of actin and vascular endothelial (VE)-cadherin to cell borders, indicating a reduction in contractile activation and stabilization of cell adhesion structures. These protective effects were blocked by genistein or Hydroxy-2-naphthalenylmethylphosphonic acid tris acetoxymethyl ester (HNMPA-[AM](3)), a pan-tyrosine-kinase or specific insulin-receptor-kinase inhibitor, respectively. Insulin stimulated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and NO production, and it activated Rac1. Inhibition of PI3K/Akt abrogated Rac1 activation and insulin-induced barrier protection, whereas inhibition of the endothelial nitric oxide synthase/soluble guanylyl cyclase pathway partially inhibited them. Inhibition of Rac1 abrogated the assembly of actin at cell borders. Accordingly, it abolished the protective effect of insulin on barrier function of the cultured endothelial monolayer, as well as the intact coronary system of ischemic-reperfused hearts.

Conclusion-Insulin stabilizes endothelial barrier via inactivation of the endothelial contractile machinery and enhancement of cell-cell adhesions. These effects are mediated via PI3K/Akt- and NO/cGMP-induced Rac1 activation. (Arterioscler Thromb Vasc Biol. 2010; 30: 1237-1245.)

Harvard Citation style: Guenduez, D., Thom, J., Hussain, I., Lopez, D., Haertel, F., Erdogan, A., et al. (2010) Insulin Stabilizes Microvascular Endothelial Barrier Function via Phosphatidylinositol 3-Kinase/Akt-Mediated Rac1 Activation, Arteriosclerosis, Thrombosis, and Vascular Biology, 30(6), pp. 1237-U363. https://doi.org/10.1161/ATVBAHA.110.203901

APA Citation style: Guenduez, D., Thom, J., Hussain, I., Lopez, D., Haertel, F., Erdogan, A., Grebe, M., Sedding, D., Piper, H., Tillmanns, H., Noll, T., & Aslam, M. (2010). Insulin Stabilizes Microvascular Endothelial Barrier Function via Phosphatidylinositol 3-Kinase/Akt-Mediated Rac1 Activation. Arteriosclerosis, Thrombosis, and Vascular Biology. 30(6), 1237-U363. https://doi.org/10.1161/ATVBAHA.110.203901