Effects of Dapagliflozin treatment on the progression of Abdominal Aortic Aneurysm in an experimental model of mice subjected to chronic infusion of angiotensin II

• Grant number: 23/14949-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2023
• End date: October 31, 2024
• Field of knowledge: Health Sciences - Medicine - Surgery
• Principal Investigator: Christiane Becari
• Grantee: Henrique Zukowski Kovacs
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 17/21539-6 - Role of renin angiotensin system in Abdominal Aortic Aneurysm, AP.JP

Abstract

Cardiovascular diseases represent the leading cause of global mortality. Among the diseases within this group is abdominal aortic aneurysm (AAA), a condition resulting from a degenerative process affecting the aortic wall, leading to its dilation. This disease is of particular concern because when an AAA ruptures, mortality is close to 90%. Studies in animals have shown that chronic infusion of angiotensin (Ang) II leads to the development of AAA, suggesting the involvement of Ang II in the disease's pathogenesis. Ang II is formed by the Renin-Angiotensin System (RAS), an enzymatic cascade involving different precursors, beginning with angiotensinogen, leading to the formation of Ang I and, subsequently, Ang II. Ang II binds to angiotensin receptors (ATR), with type 1 (AT1R) being associated with both homeostatic and pathological processes, while AT2R is related to counterregulation of the effects caused by AT1R. Furthermore, there is the formation of Ang (1-7) from Ang II, serving as another counterregulator of its effects when bound to AT1R. The counterregulatory action of Ang (1-7) occurs after its binding to the Mas proto-oncogene receptor (MasR), which is not an ATR. One possible explanation for Ang II's involvement in AAA pathogenesis is the increase in matrix metalloproteinases (MMP) 2 and MMP-9, proteases that are elevated in aneurysmal vessels, through AT1R. Sodium-glucose transporter type 2 inhibitors (SGLT2 inhibitors) are hypoglycemic drugs that have demonstrated the ability to reduce MMP-2 and MMP-9 levels. It is of interest to study whether the use of this class of medications could alter the progression of the disease, as the risk of rupture increases exponentially as the AAA diameter rises.In this Scientific Initiation project, the objective is to study the effects of Dapagliflozin treatment, an SGLT2 inhibitor, on the progression of AAA in animals subjected to chronic Ang II infusion. Experimental induction of AAA will be performed, along with the administration of Dapagliflozin or a placebo via gavage for 28 days. The animals will be divided into groups based on the treatment to which they will be subjected: I) Mice without AAA (control) treated with a vehicle; II) Mice with AAA treated with a vehicle; III) Mice without AAA (control) treated with Dapagliflozin, and IV) Mice with AAA treated with Dapagliflozin. Over the course of 28 days, the animals will be assessed weekly by ultrasound to monitor the progression of AAA. After the experiment is concluded, the animals will be euthanized, and the aorta and plasma will be collected. These materials will be used for histological analysis of the aortic wall to study structural changes, immunofluorescence analysis of components of the RAS, MMP-2 and MMP-9 in situ, and SGLT2 present in the aortic wall, as well as plasma for mass spectrometry analysis of angiotensin concentrations. This project is part of the Contribuição do Sistema Renina Angiotensina na Fisiopatologia do Aneurisma de Aorta Abdominal" project, which is funded under the Young Researcher FAPESP grant (#2017/21539-6).