Characterization of elastase-2 as an angiotensin II-forming enzyme

• Grant number: 09/52418-3
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2009
• End date: September 30, 2011
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Maria Cristina de Oliveira Salgado
• Grantee: Maria Cristina de Oliveira Salgado
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The renin-angiotensin system (RAS) is a coordinated hormonal cascade in the control of cardiovascular and renal function that controls body fluid and electrolyte balance, as well as arterial pressure. The classical RAS consists of a circulating endocrine system in which the principal effector hormone is angiotensin (Ang) II. Ang II is produced by the action of renin on angiotensinogen to form Ang I and its subsequent conversion to the biologically active octapeptide by Ang-converting enzyme (ACE). Although ACE is considered essential to Ang II formation, particularly in the vascular space, the existence of alternative pathways to ACE for Ang II generation in tissues of different species has been reported. Among the non-ACE Ang II-forming enzymes, a functional role has been attributed for the chymostatin-sensitive serine proteases, as the human chymase and rat elastase-2(ELA-2). ELA-2 is a serine protease that presents enzymologic characteristics similar to those ascribed to human chymase. Thus, a role for chymase as an alternative pathway for ACE may be overestimated in rats while ELA-2 is neglected in different tissue, including renal tissue that expresses mRNA for ELA-2. In the present project, we will investigate the role of ELA-2 in Ang II formation in the renal vasculature of normotensive and 2K1C hypertensive rats and in rats chronically treated with ACE inhibitor. Considering that rodent (rat and mouse) chymases degrade Ang II and that rat and mouse nucleotides sequences of ELA-2 present 89% identity (GenBank database), it is reasonable to assume that ELA-2 is also involved in Ang II formation in mice tissue. Therefore, we will investigate the contribution of ELA-2 in processing Ang I in mice arterial bed. Finally, we intend to produce a mouse strain in which the ELA-2 gene is deleted and investigate the consequences in the phenotype, mainly related to cardiovascular and renal structure. (AU)