Involvement of the Ca2+/ Calmodulin/CAMKII signaling axis in the electrical and contractile dysfunctions of the heart in the chronic phase of Chagas Disease

Abstract

Chagas' disease (CD) affects 6-7 million people worldwide. Among its clinical manifestations, chagasic cardiopathy is the most common and severe form and it is currently one of the main causes of heart failure (HF) and sudden death in Latin America. Chronic symptomatic patients often display hypertrophy, arrhythmias and ultimately HF, which makes the treatment ineffective, especially with combined complications. Our research group has provided solid evidences for impaired electrical, contractile and intracellular Ca2+ handling in infected cardiomyocytes. However, the molecular mechanisms that trigger the cell programming preceding such changes are still unclear. In this context, the Ca2+/Calmodulin/Calmodulin kinase II (CAMKII) signaling axis may play an important role. The hyperactivation of this axis is already linked to arrhythmias and HF. In addition, this axis is known to modulate several ion channels, transporters and contractile proteins in cardiomyocytes. In this project, we aimed to elucidate the involvement of this axis in electrical and contractile dysfunctions of the heart during the chronic phase of CD. In addition, we objective to determine if manipulation of CAMKII activity may be a promising target in the treatment of Chagas' heart disease. We are going to take advantage of our murine model of Chagas disease, which present cardiac symptoms of chronical phase at 200 days post-infection. At the and we are going to postulate whether CAMKII inhibitors are potential therapeutic agents to treat chagasic cardiomyopathy.