Role of renin angiotensin system in Abdominal Aortic Aneurysm

• Grant number: 17/21539-6
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: December 01, 2018
• End date: November 30, 2024
• Field of knowledge: Biological Sciences - Pharmacology
• Principal Investigator: Christiane Becari
• Grantee: Christiane Becari
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Edwaldo Edner Joviliano ; Helio Cesar Salgado ; Mauricio Serra Ribeiro ; Paulo Roberto Barbosa Evora ; Rodolfo Borges dos Reis
• Associated research grant(s): 19/18476-8 - Mulit-user equipment approved in grant 2017/21539-6:ODYSSEY CLX- licor, AP.EMU
• Associated scholarship(s): 23/14949-4 - Effects of Dapagliflozin treatment on the progression of Abdominal Aortic Aneurysm in an experimental model of mice subjected to chronic infusion of angiotensin II, BP.IC; 23/11789-6 - Involvement of Angiotensins in the Pathophysiology of Human Abdominal Aortic Aneurysm, BP.IC; 23/08275-0 - Plasmatic and tissue assessment of inflammatory mediators, angiotensin I and II receptors, renin, angiotensin-converting enzymes, chymase and elastase-2 in patients with and without abdominal aortic aneurysm submitted to surgery at HCRP-USP, BP.DD; + associated scholarships 22/13048-0 - Angiotensin generation profile in the aorta of mice and patients with abdominal aortic aneurysm (AAA), BP.IC; 22/02162-7 - Plasmatic and tissue assessment of inflammatory mediators, angiotensin I and II receptors, renin, angiotensin-converting enzymes, chymase and elastase-2 in patients with and without abdominal aortic aneurysm submitted to surgery at HCRP-USP, BP.MS; 21/08796-5 - CharacterizationElastase-2 knockout mice growth, mating, and genotyping analysis., BP.TT; 20/09999-4 - Biochemical characterization of angiotensin (Ang) I without plasma and aorta of C57Bl / 6 and ELA-2KO mice with abdominal aortic aneurysm (AAA) induced by the infusion of II, BP.IC; 20/03308-0 - Aorta morphological analysis of ELA-2KO mice with abdominal aortic aneurysm induced by the infusion of Angiotensin II, BP.IC; 19/24369-0 - Renin-angiotensin system molecular analyses an in the development of in the Ang-II induced aneurysm in mice, BP.IC; 19/21721-4 - Biochemical and molecular analysis of the renin-angiotensin system (RAS) components in the pathophysiology of abdominal aortic aneurysm (AAA) in patients undergoing AAA correction surgery at HCRP-USP, BP.MS; 18/23718-8 - Role of renin angiotensin system in abdominal aortic aneurysm, BP.JP - associated scholarships

Abstract

Abdominal Aortic Aneurysm (AAA) is a progressive disease leading to vascular wall deterioration and, gradual aneurysm expansion and, eventually, rupture. The incidence and mortality of AAA are high. The treatment for AAA is the open conventional repair or the Endovascular Aneurysm Repair (EVAR). There is no known effective AAA medical treatment that can inhibit its growth, development or the rupture risk in human beings. Partly, it is due to a lack of a more detailed knowledge about the genetic, cellular and humoral mechanisms in the AAA pathophysiology. The Renin-Angiotensin System (RAS) participates in several physiological and pathophysiology processes in both cardiovascular and renal systems. Experimental data show that continuous angiotensin II (AngII) infusion can induce AAA development in mice. There are also experimental and clinical evidences that the use of RAS inhibitors (angiotensin converting enzyme inhibitors- ACE inhibitors) and AT1 receptor (AT1R) antagonists can affect the aneurysm stability and reduce the rupture risk. Recently, new RAS modulation paradigms have emerged in which there might be two main RAS pathways: one ACE/Ang II/AT1R deleterious path and, a beneficial ACE-2/Ang 1-7/MASR. In addition, the biological role of other components such as Ang IV, Ang 1-9 has been characterized. Recently, the role of AT4 receptor-binding Ang IV was related as a protective factor to the development of AAA in mice. However, much of this data relating AAA and RAS peptides, including Ang II, Ang 1-7 and Ang IV, were performed on experimental animals. Little is known about the role of Ang 1-9 and Ang III, as well as on the enzymes responsible for the formation of these peptides in this context. Thus, an innovative proposal of the present research project is the investigation of the role of these important components of RAS in the development of AAA. As previously demonstrated, they can produce, degrade and regulate the different types of angiotensin. Other enzymes also participate in the generation of Ang II such as, human chymase and mice and rats elastase-2 (ELA-2). Chymase and ELA-2 contributes to the formation of Ang II in different vascular beds. Thus, as ELA-2 is an Ang II-forming enzyme in the vascular system, we intend to study the contribution this enzyme to the pathophysiology of AAA. We will use a translational approach through models in mice and surgical human samples. The infiltration of inflammatory cells and the rupture of the extracellular matrix are also involved in the formation and progression of AAA. Studies have shown that one of the mechanisms by which Ang II induces AAA is through the production and increase of the activity of the metalloproteinases (MMPs, especially MMP-2 and MMP-9) in the extracellular tissue. In addition, cytokine secretion and the accumulation of inflammatory cells in the arterial wall may contribute to the development of AAA. Therefore, the present project aims to evaluate the contribution of the components of RAS to the pathophysiology of AAA through biochemical, molecular and histological analyzes. We will use samples from patients treated on HCRP-USP and experimental models of mice (C57Bl/6 and ELA-2 knockout). The novelty of our study is the investigation of the ELA-2/chymase/ACE/AngII/AT1R, ACE-2/Ang1-7/MASR axes, the Ang4/AT4R interaction and the contribution of ELA-2 to AAA pathophysiology. Our translational approach linking clinical phenotypes of AAA patients with molecular, biochemical and histological characterization strengthens this design and enables the development of new strategies to better understand AAA in both molecular and clinical-surgical bases. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

LUIS-SILVA, FABIO; MENEGUETI, MAYRA GONCALVES; SATO, LUCAS; PERES, LEANDRO MOREIRA; SEPEDA, CORINA DOS REIS; PETROSKI-MORAES, BRUNO C.; DONADEL, MARIANA DERMINIO; GALLO, GABRIELA BORTOLETO; JORDANI, MARIA CECILIA; MESTRINER, FABIOLA; et al. Effect of methylene blue on hemodynamic response in the early phase of septic shock: A case series. MEDICINE, v. 102, n. 4, p. 7-pg., 2023-01-27. (18/26553-0, 17/21539-6, 18/23718-8, 21/01195-6)

BECARI, CHRISTIANE; PEREIRA, GIORGIA LEMES; OLIVEIRA, JOSE A. C.; POLONIS, KATARZYNA; GARCIA-CAIRASCO, NORBERTO; COSTA-NETO, CLAUDIO M.; PEREIRA, MARILIA G. A. G.. Epilepsy Seizures in Spontaneously Hypertensive Rats After Acoustic Stimulation: Role of Renin-Angiotensin System. FRONTIERS IN NEUROSCIENCE, v. 14, DEC 23 2020. (18/23718-8, 17/21539-6)

POLONIS, KATARZYNA; BECARI, CHRISTIANE; CHAHAL, C. ANWAR A.; ZHANG, YUEBO; ALLEN, ALINA M.; KELLOGG, TODD A.; SOMERS, VIREND K.; SINGH, PRACHI. Chronic Intermittent Hypoxia Triggers a Senescence-like Phenotype in Human White Preadipocytes. SCIENTIFIC REPORTS, v. 10, n. 1, APR 22 2020. (18/23718-8, 17/21539-6)