Role of the caspase-1 in age-associated cardiac changes (structural and functional). Possible involvement of the AIM2 inflammasome

• Grant number: 22/00840-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2022
• End date: September 30, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Maria Luiza de Morais Barreto de Chaves
• Grantee: Nathalia Senger
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 19/17031-2 - Inflammasome in the cardiac physiopathology, AP.TEM
• Associated scholarship(s): 23/01217-5 - Role of macrophages in thyroid hormone-induced cardiac hypertrophy, BE.EP.PD

Abstract

Given that cardiovascular diseases represent the first cause of morbidity and mortality in humans, the importance and relevance of new studies is highlighted. In this context, understanding the molecular mechanisms involved in cardiac hypertrophy has been of great interest, since cardiac hypertrophy precedes almost all forms of heart failure. In addition, cardiac hypertrophy is an independent risk factor for myocardial infarction and sudden death. Regarding molecular mechanisms, the increase of pro-inflammatory cytokines, because of inflammasome activation, has been pointed out as a determining mechanism of cardiac prognosis. In this sense, the canonical inflammasomes (NLRP1, NLRP3, NLRC4 e AIM2) correspond to a cytoplasmic sensor that, when activated, form a multiprotein complex and result in activation of caspase-1 and, consequently, secretion of pro-inflammatory cytokines and cell death by pyroptosis. Although the role of these inflammasomes has been widely studied in different models of cardiovascular diseases, little is known in the aging model. Interestingly, cardiac tissue in the aged exhibits an increased inflammatory response, termed "inflammaging," in which senescent cardiac cells secrete an array of pro-inflammatory cytokines. In this context, the main aim of the present study is to investigate whether the inflammasome may represent a mediator of cardiac alterations (structural and functional) that affect the aging. For this, mice deficient for caspase-1 (casp1-/-) will be used in order to evaluate the general participation of the different types of inflammasomes. In parallel, since the AIM2 inflamasome is particularly activated by double-stranded DNA, mice deficient for AIM2 (Aim2-/-) will also be used in order to ascertain the specific role of this inflammasome. This topic of study becomes promising since damage to mitochondrial and nuclear DNA is commonly observed in senescent cardiomyocytes, which could hypothetically contribute to the activation of AIM2 in the aging model. Furthermore, aiming at a translational approach, in vitro experiments will also be performed using senescent human cardiomyocytes (AC16 strain). Among the proposed methodologies, new experimental techniques to evaluate aging, oxidative stress and inflammation will be implemented in the laboratory, which will allow an important methodological advance for our research group.