Increased complement system and reduced regulatory T cells may increase the activity of matrix metalloproteinase (MMP)-2 and arterial remodeling in hypertension

Author(s)

Luan Victor Resque Ramos

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2024-04-22

Examining board members

Michele Mazzaron de Castro; Stefany Bruno de Assis Cáu; Silvia Lacchini

• Advisor: Michele Mazzaron de Castro

Abstract

Hypertension is associated with inflammation, so that hypertensive patients have higher plasma concentrations of pro-inflammatory cytokines. The generation of reactive oxygen species (ROS), the expression and release of cytokines and chemokines and the infiltration of immune cells in the kidneys and arteries are characteristic of hypertension. Oxidative stress may play a role in regulating the immune response in hypertension by activating the complement system and reducing regulatory T cells (Tregs). The complement system, in turn, physiologically decreases the expression and function of circulating Tregs in vivo, so that an increase in its activity results in inhibition of the suppressive capacity of this population of cells and in oxidative stress, suggesting an inter-relationship between the components of this pathway. Furthermore, oxidative stress is capable of increasing the activity of MMP-2, which is important for arterial remodelling in hypertension, while the complement system increases the expression of MMP-2 in an animal model of aneurysm. Knowing that there is an increase in the complement system in hypertension, the hypothesis is that the increase in the complement system C3a contributes to increasing oxidative stress, reducing Tregs and increasing the activity and expression of MMP-2, which results in arterial remodelling in hypertension. Hypertension was induced in C57BL/6 mice by infusion of angiotensin-II by osmotic minipumps, and they were treated with the C3aR antagonist SB290157. Blood pressure was assessed by tail and invasive plethysmography and the expression of Foxp3, C3a, C3aR, MMP-2, IL-6 and IL-10 was determined by Western Blot and Elisa; MMP-2 activity was determined by gel and in situ zymography and oxidative stress by DHE; analysis of arterial remodelling was also assessed by haematoxylin and eosin staining; CD4 and Foxp3 staining was used in flow cytometry. Systolic blood pressure was higher in the hypertensive group compared to the Sham group (p<0.05), and the treatment was effective in lowering SBP on the last day of treatment by the non-invasive method; however, by the invasive method, there was no difference. The hypertensive group also obtained higher values of pro-inflammatory cytokines than the Sham group. There was no significant difference between the groups in terms of C3aR protein content. The hypertensive group also had higher plasma C3a values (p<0.05) than the Sham group. By analysing aortic content, MMP-2 activity was increased in the hypertensive group and the drug was able to decrease activity (p<0.05). The increase in C3a resulting from the onset of hypertension has the effect of worsening hypertension and increasing MMP-2 activity, which can be attenuated with the use of the drug. (AU)

• FAPESP's process: 23/04177-4 - Increase in the complement system and reduction in T regulatory cells may increase the activity of matrix metalloproteinase(MMP)-2 and arterial remodelling in hypertension
• Grantee: Luan Victor Resque Ramos
• Support Opportunities: Scholarships in Brazil - Master