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Simvastatin Improves Cardiac Function through Notch 1 Activation in BALB/c Mice with Chronic Chagas Cardiomyopathy
Daniela Guzmán-Rivera1, Ana Liempi2, Fabiola González-Herrera1
1Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
Insights
Simvastatin treatment improved cardiac function in Chagas disease mice by activating the Notch pathway, reducing inflammation and fibrosis. This suggests statins may offer a new therapeutic approach for chronic Chagasic cardiomyopathy.
Area of Science:
- Cardiology
- Parasitology
- Pharmacology
Background:
- Chagas disease, caused by *Trypanosoma cruzi*, leads to chronic inflammatory cardiomyopathy and heart failure.
- Current treatments fail to halt or reverse heart damage progression in Chagas disease.
- Statins possess pleiotropic effects, including potential modulation of inflammation and angiogenesis.
Purpose of the Study:
- To investigate simvastatin's therapeutic potential in reversing chronic heart damage in a mouse model of Chagas disease.
- To explore the role of the Notch pathway in simvastatin's effects on chagasic myocarditis.
Main Methods:
- BALB/c mice chronically infected with *T. cruzi* were treated with simvastatin or 15-epi-lipoxin A4.
- Cardiac function was assessed via echocardiography.
- Notch 1 pathway activity, angiogenesis (isolectin B4 staining), inflammation, fibrosis, and parasitic load were evaluated in heart tissues.
Main Results:
- *T. cruzi* infection activated the Notch 1 pathway.
- Simvastatin significantly increased Notch 1 activity, improved ejection fraction, and reduced cardiac inflammation and fibrosis.
- Simvastatin promoted angiogenesis without altering parasitic load; 15-epi-lipoxin A4 did not yield similar benefits.
Conclusions:
- Simvastatin, likely via Notch 1 pathway activation, ameliorates cardiac dysfunction and pathology in chronic Chagas disease.
- Statins represent a promising therapeutic strategy for managing chronic chagasic cardiomyopathy.
Abstract:
Chagas disease, caused by the protozoan Trypanosoma cruzi, endemic in Latin America but distributed worldwide because of migration. Without appropriate treatment, the disease progresses from an acute asymptomatic phase to a chronic, progressive inflammatory cardiomyopathy causing heart failure and death. Despite specific trypanocidal therapy, heart damage progression cannot be stopped or reversed. Statins, as part of their pleiotropic actions, can modulate chagasic myocarditis by inducing the production of 15-epi-lipoxin A4 (15-epi-LXA4), a proresolution lipid mediator in inflammation. Furthermore, several reports suggest that simvastatin activates the Notch pathway after stroke in cerebral endothelial cells, enhancing blood flow by promoting angiogenesis. Thus, statins are an attractive therapeutic strategy for modulating the Notch pathway to reverse the chronic heart damage induced by T. cruzi BALB/c mice chronically infected with T. cruzi were treated with 1 mg/kg/day simvastatin or 25 μg/kg/day 15-epi-LXA4 for 20 days. During the treatment period, cardiac function was evaluated by echocardiography. At 80 days postinfection, the heart tissues were assessed for Notch 1 activity. T. cruzi infection activated the Notch 1 pathway, and simvastatin (but not 15-epi-lipoxin A4) produced a further increase in that activity, correlating with improvement in the ejection fraction and histopathologic findings typical of T. cruzi infection, including improvements in inflammation and fibrosis. Moreover, simvastatin increased the number of isolectin B4-positive cells, suggesting active angiogenesis in the chronically infected hearts without alteration of the parasitic load. Simvastatin, probably acting through the Notch 1 pathway, decreases inflammation, improving cardiac function in mice chronically infected with T. cruzi.
