Caractérisation des processus moléculaires impliqués dans l’activation de la protéine IKKbeta par l'angiotensine II et son rôle dans la réponse phénotypique des CMLV
The renin-angiotensin-aldosterone system (RAAS) plays an essential role in the homeostatic control of arterial pressure through its influence on the vascular smooth muscle cells (VSMC) contraction-relaxation cycle. Nevertheless, activation of the AT1 receptor by angiotensin II (Ang II) is also involved in VSMC inflammation and hypertrophy. The latter are two processes related to arterial remodeling which is the culprit of some cardiovascular diseases such as hypertension and atherosclerosis. These diseases are the leading cause of natural death in America and the treatments available to date are not optimum because they target only some and not all risk factors associated to it. Thus, determination of the intracellular effectors involved in these deleterious signaling pathways is needed to identify new therapeutic targets.  Ang II-induced inflammation in VSMC is under the control of the transcription factor nuclear factor-kappa B (NF-κB). However, the molecular mechanisms coupling the AT1 receptor to its activation are not well characterized. The study addressing this issue demonstrates in vitro that the activation of NF-kB is dependent of the activation of IκB kinase β (IKKβ) in VSMC. This kinase is regulated by two independents, but complementary signaling pathways to insure its vigorous and sustained activation. One of them is an early event that relies on second messengers and two novel effectors of the AT1 receptor, the E3 ligase TNF receptor-associated factor 6 (TRAF6) and the IKK kinase transforming growth factor-beta-activated kinase 1 (TAK1). The other pathway is delayed and relies on the- mitogen-activated protein kinase kinase 1/2 (MEK1/2) - extracellular signal-regulated kinase 1/2 (ERK1/2) - ribosomal S6 kinase (RSK) axis. Moreover, inhibition of both pathways completely abolishes the Ang II-induced inflammatory response in VSMC which indicates that they are the only one implicated. Thus, inhibition of IKKβ would be possibly sufficient to compromise the inflammation implicated in the development of vascular remodeling. One of the innovative discoveries that has emerged from this latest study is that the E3 ligase TRAF6 is a G protein-coupled receptors effector responsible for the formation of a new type of second messengers described as free poly-ubiquitin chains. Regarding the Ang II-induced hypertrophic response, the molecular mediators involved in protein synthesis are also poorly defined. However, it has been shown that IKKβ has the ability to control the initiation of translation in response to tumor necrosis factor α (TNFα) by its capacity to phosphorylate the protein Tuberous sclerosis 1 (TSC1) and then to activate the mammalian target of rapamycin complex (mTORC1) in cancer cells. Therefore, some in vitro experiments have been conducted in VSMC to determine whether IKKβ also contributes to this phenomenon in response to Ang II. Indeed, in VSMC exposed to Ang II, IKKβ has the ability to induce the phosphorylation of TSC1 and the activation of mTORC1 as well as its downstream effectors S6 kinase 1 (S6K1) and translational regulators eukaryotic  translation initiation factor 4E-binding protein (4E-BP1), proteins related directly to hypertrophy. Furthermore, Ang II-induced protein synthesis in VSMC is drastically reduced following a decrease in the expression of IKKβ and following the overexpression of a mutant of TSC1 in which the consensus site of IKKβ has been modified.  Thus, IKKβ acts upstream of two processes involved in the development of cardiovascular diseases related to vascular remodeling in response to Ang II in vitro. In addition, most of their risk factors converge to the activation of IKKβ making it an attractive therapeutic target. Moreover, this kinase is a protein of interest for the translational research, since the administration of an IKKβ inhibitor to rats reduces not only the Ang II-induced protein synthesis in the aorta and mesenteric arteries, but also the synthesis of the pro-inflammatory protein VCAM -1.
Hypertension Inflammation TRAF6 TAK1 IKKβ NF-κB TSC1 mTOR Atherosclerosis Vascular remodeling Hypertrophy Angiotensin II