Role of SOC3 protein on the angiotensin II intracellular and the molecular cross-talk between angiotensin II and signaling in cardiac tissue of rats

Author(s)

Vivian Cristine Calegari

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2006-02-06

Examining board members

Licio Augusto Velloso; Francisco Rafael Martins Laurindo; Marcio Alberto Torsoni; Wilson Nadruz Junior; Everardo Magalhães Carneiro

• Advisor: Licio Augusto Velloso

Abstract

Intracellular interactions between different signaling systems may function as mechanisms for enhancing or counter-regulating hormone action. The hormone angiotensin II (ANGII) is involved in the development of both, hypertension and insulin resistance. Several studies demonstrate that in signaling systems that use the JAK/STAT pathway, proteins of the suppressor of cytokine signaling (SOCS) family participate in signal regulation. In the present study we demonstrate that ANGII is able to activate the JAK/STAT pathway and, subsequently, the expression of SOCS3. SOCS3 is constitutively expressed at a low level in the heart of rats and neonatal rat ventricular myocytes. ANGII, at a physiological concentration, enhances the expression of SOCS3 mRNA and protein, mainly via AT1 receptors. After induction, SOCS3 associates with JAK2 and impairs further activation of the JAK2/STAT1 pathway. Pretreatment of rats with a specific phosphorthioate antisense oligonucleotide against SOCS3, reverses the desensitization to angiotensin signaling, as detected by a fall in c-jun expression after repetitive infusions of the hormone. We also demonstrate the interaction of ANGII-induced SOCS3 with the insulin signaling pathway in cardiac tissue in vivo and in isolated cell system. ANGII-induced SOCS3 interacts with the IR, JAK2, IRS1 and IRS2. The inhibition of SOCS-3 expression by antisense oligonucleotide partially restores the ANGII-induced inhibition of insulin-induced IR, IRS- 1 and IRS-2 tyrosine phosphorylation, IRS1 and IRS2 association with p85- phosphatidylinositol 3-quinase and AKT [Ser473] serine phosphorylation. Moreover, the inhibition of SOCS3 expression partially reverses ANGII- induced inhibition of insulinstimulated GLUT-4 translocation to the cell membrane. Thus, ANGII-induced SOCS3 in rat heart and neonatal rat ventricular myocytes may actively participate in the control of the ANGII signaling, and also, as a late event, in the negative cross-talk between ANGII and insulin signaling pathways (AU)