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Inflammasome in the cardiac physiopathology


Cardiovascular diseases remain the leading cause of global morbidity and mortality today. Even considering the scientific and technological advances of the last two decades, it is estimated that in 2030 more than 23 million people will die due to cardiovascular diseases. Although different stimuli may induce heart failure (HF), it is preceded by cardiac hypertrophy, characterized by increased cardiomyocyte volume and consequently increased left ventricle thickness. Several groups, including ours, have been demonstrating that, like other chronic diseases, the cardiomyocyte hypertrophic phenotype is associated to mechanisms related to inflammation. Thus, there is a growing interest today in investigating which contribution and what specific local stimuli in the "cardiomyocyte environment" are responsible for the activation of specific signaling pathways selectively implicated in the transition from adaptive/compensated cardiac hypertrophy to a decompensated/pathologic phenotype, leading to HF. Then, the identification of new signaling pathways and mechanisms responsible for the activation of inflammatory factors associated to HF, such as IL-1² and IL-18, may contribute to new therapeutic targets resulting in slower progression of disease. After synthesized in cardiac cells, these inflammatory factors are activated via inflammassome, a multi-protein complex formed by different elements (NLRs, ASC and Caspase-1) and then they are released to extracelular space. The hypothesis of this study is that the inflammassome may function as an important mediator in the pathogenesis of cardiac hypertrophy that precedes HF. Thus, this project aims to study the participation of NLRs, ASC adapter molecule and Caspase-1 in the pathogenesis of compensated/physiological and decompensated/pathological cardiac hypertrophy using transgenic murine models and/or human cardiomyocyte cell cultures. The knowledge acquired about aspects involving the innate immune responses will contribute for our understanding concerning mechanisms related to the progression of cardiac hypertrophy, besides enabling studies directed to the development of new methodologies and therapeutic strategies that attenuate progression to HF. (AU)

Articles published in Agência FAPESP Newsletter about the research grant: