Potential cardioprotective role of Type 2 Angiotensin II Receptor (AT2) in aging-associated to cardiac senescence: possible involvement of inflammasomes.

Author(s)

Larissa Maria Zacarias Rodrigues

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2024-06-07

Examining board members

Maria Luiza de Morais Barreto de Chaves; Silvia Carolina Guatimosim Fonseca; Luciana Venturini Rossoni; Carlos Renato Tirapelli

• Advisor: Maria Luiza de Morais Barreto de Chaves; Ana Paula Cremasco Takano

Abstract

The heart is subject to different pathophysiological stimuli, which can lead to the development of cardiovascular diseases. Aging corresponds to one of the risk factors for these diseases, with the activation of inflammatory cascades and protein complexes called inflammasomes, in addition to the synthesis and release of cytokines. Furthermore, there is the production of reactive oxygen species and the activation of senescence pathways, which leads to structural and functional changes in the heart. One of the systems that directly affects cardiac function and morphology is the renin-angiotensin system (RAS). Its main effector is Ang II, which, when binding to AT1 and AT2 receptors, produces, for the most part, antagonistic responses. Thus, hypertrophic and inflammatory responses are associated with AT1 and cardioprotective responses with AT2. The hypothesis of the present study is that the AT2 receptor exerts cardioprotective effects in aging and that its suppression triggers the activation of inflammatory processes, with the activation of inflammasomes, which contributes to the inflammatory phenotype associated with aging. To test it, we used wild-type mice (WT C57BL/6) or knockouts for the AT2 receptor, aged 4-5 months (young) or 18 months (elderly). During aging, we observed a reduction in the survival of KO-AT2 mice, a significant increase in cardiac trophism, increased tissue fibrosis and impairment of diastolic function, and senescence markers p53 and p21 (vs aged WT), as well as increased gene expression of pro-inflammatory cytokines. We did not observe an increase in the expression of DNA damage markers (p-H2AX) and changes in telomere length. Furthermore, no redox changes were seen in the experimental groups. Our findings suggest the participation of the AT2 receptor in mitigating pathological processes associated with aging in cardiac tissue and its absence accelerates these effects during aging. (AU)

• FAPESP's process: 22/00057-1 - Potential cardioprotective role of angiotensin II receptor type 2 (AT2) in aging-associated cardiac senescence: possible involvement of inflammasomes
• Grantee: Larissa Maria Zacarias Rodrigues
• Support Opportunities: Scholarships in Brazil - Master