Simvastatin Improves Cardiac Function through Notch 1 Activation in BALB/c Mice with Chronic Chagas 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.

Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy

“…So, we can raise the hypothesis that a down expression of NOTCH1 in CCC patients promote the Th1 response associated to severe cardiomyopathy. To support this hypothesis, Guzmán-Rivera et al had treated Chagas infected mice with simvastatin ( 77 ). Simvastatin activates the Notch 1 pathway in the hearts of T.cruzi infected mice and decreases the cellular infiltrate, inflammatory cytokines and prevents the increase in collagen deposition in cardiac tissue.…”

Therapeutic Effects of Specialized Pro-Resolving Lipids Mediators on Cardiac Fibrosis via NRF2 Activation

“…Compared to the effects of DHA and EPA on improving cardiac fibrosis, there are few reports on the therapeutic effect on cardiac fibrosis by pro-resolving lipids mediators derived from them. Chagas disease, caused by the protozoan Trypanosoma cruzi , progresses to chronic progressive inflammatory cardiomyopathy, which leads to heart failure and death during the acute asymptomatic stage if an appropriate treatment is not administered [ 205 ]. Statins can regulate chagasic myocarditis by inducing the production of 15-epi-lipoxin A4 (15-epi-LXA4), a pro-resolving lipid mediator in inflammatory cardiomyopathy.…”

Statins change the cytokine profile in Trypanosoma cruzi-infected U937 macrophages and murine cardiac tissue through Rho-associated kinases inhibition

“…Thus, as part of their pleiotropic actions, statins may inhibit ROCK activity in immune cells of atherosclerosis patients ( 22 ) and promote M2 macrophage polarization in patients with coronary artery disease ( 23 ). We previously demonstrated the effect of statins in decreasing cardiac tissue inflammation and fibrosis in mouse models of chronic Chagas cardiomyopathy ( 24 , 25 ). However, the impact of T. cruzi infection on macrophage polarization and its relationship with ROCK activity has not been studied yet.…”