Consecuencias estructurales y funcionales de la deleción condicional de la quinasa ligada a integrinas (ILK) en animales adultos

Abstract

Integrin‐linked kinase (ILK) is an intracellular effector of cell‐matrix interactions and regulates many cellular processes, including growth, proliferation, survival, differentiation, migration, invasion and angiogenesis. Although its role has been wide studied during the development, little is known about its function in tissue function and reparation in adult animals. With the objective to analyze the ILK role in tissue homeostasis, adult mice with conditional knock‐out of the ILK gene were generated with the Cre‐lox system. First, the consequences of the ILK deletion in the vascular function were analyzed. The ILK deficient mice show an increase in two proteins in the vascular aortic wall involved in cellular response to nitric oxide, the guanylyl cyclase and the protein kinase G (PKG). This increase does not affect to the basal values of systolic pressure but leads to an enhanced response to the nitric oxide (NO) donnors and cGMP analogues. Further, these animals were able to restore the isosorbide dinitrate tolerance to NO donnors and promote a decrease arterial pressure in response to sodium nitropruside (SNP) administration, which was not shown in the animals with intact ILK. The enhance SNP response was also higher in the ILK deficient mice after angiotensin II‐induced hypertension. In second place, the ILK implication in tissue reparation was studied choosing a cutaneous wound healing model. ILK deficiency leads toward decreased wound healing closure in skin and decreased cell proliferation, showing that its activation is necessary in tissue reparation. This deceleration seems to be due to a decrease HGF protein expression during wound healing. Significantly, alterations in cell proliferation and forward wound closure could be rescued by exogenous administration of human HGF plasmid in the ILK‐deficient mice. The analysis of the intracellular mechanisms involved in this process reveal that wound promotes to a rapid activation of PI3kinase and ILK, necessary to the increase of HGF expression during the wound healing. Herein, PI3kinase seems to play a central role in the ILK modulation which, at its turns, plays a pivotal role in HGF synthesis. In conclusion, the activation of ILK seems to be decisive to start the mechanisms of tissue reparation dependent on HGF overexpression.