Program

OR18-4

SIMVASTATIN AND 15-EPI-LIPOXIN A4 INDUCE CARDIAC REPAIR THROUGH NOTCH 1 ACTIVATION IN CHRONIC CHAGAS CARDIOMYOPATHY

[Speaker] Daniela Guzman-Rivera:1
[Co-author] Fabiola Gonzalez-Herrera:1, Michel Lapier:1, Ileana Carrillo:1, Barbara Pesce:1, Christian Castillo:2, Ana Liempi:2, Sebastian Fuentes-Retamal:1, Ulrike Kemmerling:2, Juan Diego Maya:1
1:Molecular and Clinical Pharmacology Program, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Chile, 2:Program of Anatomy and Developmental Biology, Biomedical Sciences Institute (ICBM), Faculty of Medicine, Chile

Background: Chagas Disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America, and worldwide because of migration. Without appropriate treatment, this disease progress from an acute, asymptomatic, to a chronic phase that, in some patients, affects the heart. Chronic Chagas Cardiomyopathy (CCC), the most severe clinical manifestation of the chronic phase, involves a progressive inflammatory myocarditis that affects the ventricular wall causing cardiovascular complications due to diminished cardiac function and heart failure. Despite intense research on new trypanocidal therapy, no one drug can stop or reverse the progressive heart damage. Simvastatin, a drug that decreases blood cholesterol, has anti-inflammatory effects and inhibits platelet aggregation. Previously, our group described that simvastatin improves endothelial function and reduces myocardial inflammation caused by T. cruzi through 15-epi-lipoxin A4 production, a pro-resolutory molecule of inflammation. Several reports suggest that simvastatin activates Notch pathway after a stroke in cerebral endothelial cells enhancing blood flow by promoting angiogenesis. CCC progress with myocardial inflammation, endothelial damage with micro focal ischemia and fibrosis. Therefore, an attractive therapeutic strategy is to search for drugs modulating Notch pathway to revert the heart damage induced by T. cruzi. Thus, we propose that 15-epi-lipoxin A4, induced by simvastatin, reverts cardiac damage in the chronic T. cruzi infection by Notch 1 pathway activation.
Methods: BALB/c mouse were chronically infected with T. cruzi Dm28c strain and treated with simvastatin 1 mg/Kg/day and 15-epi-lipoxin A4 25 ug/Kg/day for 20 days. At day 80 post-infection (p.i.) cardiac function was analyzed by echocardiography, and at day 120 p.i., animals were euthanized to analyze the heart, Notch pathway and fibrosis through immunofluorescence and immunohistochemistry.
Results: In chagasic mice, the cardiac function was restored with simvastatin and 15-epi-lipoxin A4 treatment. The Notch signaling pathway was active in cardiac tissue, a finding that correlated with drug treatment. Cardiomyocyte proliferation and angiogenesis was also evidenced in this model.
Conclusion: Thus, we concluded that simvastatin and 15-epi-lipoxin A4 improve cardiac architecture and function through Notch 1 activation by increasing blood flow and decreasing cardiac remodeling. Thus, it could be incorporated rapidly in CCC treatment.
Acknowledgements: FONDECYT 1170126, 3160022, and CONICYT 21151001.
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