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Molecular mechanisms involved in the desensibilization of ± adrenergic receptors during Sepsis: potential for the treatment of Vasoplegia

Grant number: 20/08109-5
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): September 01, 2020
Effective date (End): November 07, 2022
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Fernando de Queiroz Cunha
Grantee:Letícia Selinger Galant
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID


Sepsis is a complex syndrome triggered by a systemic inflammatory response to an infectious. It is characterized by of inflammatory, metabolic and hemodynamic events, such as: increased systemic concentrations of inflammatory mediators, leukocyte activation, lactic acidosis, cardiovascular collapse characterized by loss of vascular tone (Vasoplegia), leading to hypotension and hypoperfusion of tissues/organs (Dellinger et al., 2013; Duan et al., 2015). In some cases, the Sepsis-induced Vasoplegia is refractory to fluid resuscitation, leading to vital organ failure and septic shock (Gamcrlidze et al., 2015; Geloen et al., 2015). The treatment for this condition is based on the administration of vasopressors and norepinephrine being one of the main agents used (Geloen et al., 2015). Noradrenaline exerts its vasopressor effects through the activation of a1 adrenoceptors present in the smooth muscle of vessels (Bangash et al., 2012). The a1-adrenoceptors are divided into three subtypes (a1A, a1B and a1D) and all of them activate Gq/11 protein to stimulate intracellular calcium (Ca2 + i) mobilization and the activation of protein kinase C (PKC), leading to the contraction of vascular smooth muscle (Amberg & Navedo, 2013). Clinical evidence has shown vascular hyporesponsiveness in severe septic shock, despite high plasma levels of endogenous and/or exogenous catecholamines, which reduces the effectiveness of treatment and increases the mortality rate of patients (Levy et al., 2010; Geloen et al., 2015). The exact mechanism responsible for catecholaminergic hyporesponsiveness in Sepsis remains to be elucidated, but it is believed that the a1-adrenoceptor desensitization could be responsible for the lack of vasopressor responses to catecholamines in septic shock (Ghosh & Liu, 1983; Hwang et al., 1994; Geloen et al., 2015). The desensitization of a1 adrenoceptors is a process that can be independent of G protein and with involvement of the b-arrestin signaling pathway, which induce the internalization of receptors (Stanasila et al., 2008; Akinaga et al., 2013; Pupo et al., 2016). In this context, recent evidence has shown that certain ligands of G protein-coupled receptors can preferentially activate one signaling pathway over another (biased agonism), with important consequences in clinical practice (Rajagopal et al., 2010; Kenakin & Christopoulos, 2013). In addition, molecular events stimulated by inflammatory mediators also contribute to the a1-adrenoceptor receptor desensitization. Thus, this study aims to evaluate in vitro and in vivo the biased agonism of classic ligands of a1-adrenoceptor, identifying compounds that have a preference for the Gq/11 Protein pathway (Ca2 + mobilization, vasoconstriction) compared to the pathway of b-arrestins (internalization of receptors/desensitization) in control and severe Sepsis situation. It is also intended to identify the main molecular pathways involved in desensitizing the receptors. From this, it is intended to investigate whether pharmacological inhibition or genetic deletion of components of these molecular pathways prevents the observed Vasoplegia in Sepsis. The results of this study will indicate more efficacious compounds for the treatment of Sepsis-induced Vasoplegia, improving the outcome and survival of patients with septic shock. (AU)

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