Angioedema and bradykinin receptors in the endothelium

• Grant number: 19/06543-2
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2019
• End date: August 31, 2022
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Agreement: DAAD
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: João Bosco Pesquero
• Grantee: João Bosco Pesquero
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 14/27198-8 - Establishment of a center of genetic and molecular research for clinical challenges, AP.TEM

Abstract

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by C1 esterase inhibitor (C1-INH) quantitative (type I) or functional (type II) deficiency, with more than 500 mutations identified (The Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). C1-INH is a secreted glycoprotein of the serpin family that inhibits several proteases of the classical and lectin complement pathways (Ricklin et al., 2010), and other serine proteases as plasma kallikrein (KK), coagulation factors XI (FXI) and XII (FXII), thrombin, plasmin and tissue plasminogen activator (Sainz et al., 2007). Its deficiency results in an uncontrolled bradykinin (BK) release due to high molecular weight kininogen (HMWK) cleavage by KK activity. BK exerts a strong increase in vascular permeability and is therefore recognized as the main responsible factor for HAE symptoms. HAE clinical description and hereditary characteristic was established in the 19th century (Quincke, 1882; Osler, 1888), but only in 1960s-decade C1-INH deficiency was identified (Donaldson and Evans, 1963). The characteristic symptoms are nonpruritic and nonpitting swellings of submucosal or subcutaneous tissues involving face, hands, feet, arms, legs, bowels, genitalia and life-threatening upper airways edema episodes (Longhurst and Cicardi, 2012). Angioedema symptoms generally last 2 to 5 days and most common triggering factors for HAE attacks include emotional stress, trauma, medical and surgical procedures, and estrogens (Busse and Buckland, 2013; Joseph et al., 2016). Despite angioedema episodes resolve spontaneously without treatment, the clinical expression is highly variable among the patients, from asymptomatic cases to patients suffering from disabling and life-threatening laryngeal attacks with a demonstrated humanistic and economic burden (Cicardi et al., 2012). Besides the hereditary forms of angioedema, such attacks can also be elicited by medicaments, such as inhibitors of angiotensin-converting enzyme, ACE, which are very common antihypertensive drugs and inhibitors of dipeptidyl peptidase IV (DPPIV), which are novel antidiabetic drugs. ACE and DPPIV inhibit BK degradation and thereby their inhibition can induce BK accumulation and angioedema. BK has two receptors, BKB1 and BKB2. The BKB2 receptor is thought to be mainly responsible for angioedema attacks since it is permanently expressed in vascular endothelium. Nevertheless, the BKB1 receptor, which is induced by inflammation, may contribute in certain disease states. In both cases the signaling pathways employed by the two receptors are incompletely understood. Several drugs are currently available for treating and preventing angioedema attacks. A novel approach to stop the progression of acute attacks is the administration of BKB2 receptor antagonists (icatibant) (Bas et al., 2015). However, all of the current treatments have potential shortcomings as difficult administration (Banerji et al., 2017), high costs and/or variable individual efficacy (Longhurst and Bygum, 2016). We will use novel transgenic rat models overexpressing BKB1 and BKB2 receptors specifically in the endothelium of vessels to study the mechanism by which these receptors mediate angioedema attacks. The results may help to define novel therapeutic targets for this disease.This project is inserted in the context of the Subproject I from Thematic Project "Establishment of a center of genetic and molecular research for clinical challenges" (2014/27198-8), whose objectives involve the study of HAE. The animal models for this project were generated in previous collaboration between the proponent groups. (AU)