Simvastatin Attenuates Endothelial Activation through 15-Epi-Lipoxin A4 Production in Murine Chronic Chagas Cardiomyopathy

Abstract

Current treatments for chronic Chagas cardiomyopathy, a disease with high mortality rates and caused by the protozoan Trypanosoma cruzi, are unsatisfactory. Myocardial inflammation, including endothelial activation, is responsible for the structural and functional damage seen in the chronic phase. The clinical efficacy of benznidazole could be improved by decreasing chronic inflammation. Statins, which have anti-inflammatory properties, may improve the action of benznidazole. Here, the action of simvastatin in a murine model of chronic Chagas cardiomyopathy and the link with the production of the proresolving eicosanoid 15-epi-lipoxin A4, produced by 5-lipoxygenase, are evaluated. Simvastatin decreased the expression of the adhesion molecules E-selectin, intracellular adhesion molecule type 1 (ICAM-1), and vascular cell adhesion molecule type 1 (VCAM-1) in T. cruzi-infected mice. However, when this drug was administered to 5-lipoxygenase-deficient mice, the anti-inflammatory effect was not observed unless exogenous 15-epi-lipoxin A4 was administered. Thus, in chronic Chagas disease, 5-epi-lipoxin A4 induced by simvastatin treatment could improve the pathophysiological condition of patients by increasing the trypanocidal action of benznidazole.

Keywords: 15-epi-lipoxin A4; 5-lipoxygenase; CAM; Chagas disease; chronic cardiomyopathy; simvastatin.

FIG 1

Parasitemia (A) and survival (B) progression in BALB/c and Sv/129 wild-type (WT) or 5-lipoxygenase (5-LO^−/−) knockout mice. Bars in panel A correspond to the standard deviations from three independent experiments. ***, P < 0.001.

FIG 2

Representative photographs of immunohistochemically stained cardiac tissue from BALB/c mice infected with Dm28c Trypanosoma cruzi and treated with simvastatin or benznidazole at the indicated doses. Insets show healthy noninfected murine cardiac tissue. Sim, simvastatin; Bz, benznidazole.

FIG 3

Representative photographs of hematoxylin and eosin-stained (A) or picrosirius red-stained (B) cardiac tissue from BALB/c mice infected with Dm28c Trypanosoma cruzi and treated with simvastatin or benznidazole at the indicated doses. Insets show healthy noninfected tissues. Sim, simvastatin; Bz, benznidazole.

FIG 4

Levels of 15-epi-lipoxin A4 in sera of Sv/129 mice infected with Trypanosoma cruzi. ELISAs were performed at 80 dpi. Bars correspond to the standard deviations for three independent experiments. ***, P < 0.001.

FIG 5

(A) Representative images of cardiac tissue immunohistochemically stained for E-selectin, ICAM-1, and VCAM-1 from Sv/129 wild-type or 5-LO KO mice infected with Dm28c Trypanosoma cruzi and treated with simvastatin or 15-epi-lipoxin A4 at the indicated doses. (B) Levels of soluble E-selectin, ICAM-1, and VCAM-1 in serum. Insets show healthy noninfected murine cardiac tissue.

FIG 6

Representative photographs of hematoxylin and eosin-stained (A) or picrosirius red-stained (B) cardiac tissue from Sv/129 mice infected with Dm28c Trypanosoma cruzi and treated with simvastatin or 15-epi-lipoxin A4 at the indicated doses. Insets show healthy noninfected murine cardiac tissue. *, P < 0.05.

FIG 7

Parasite load in heart tissue of mice chronically infected with Trypanosoma cruzi and euthanized at 90 (A) or 80 (B) dpi. Bars correspond to the standard deviations for three independent experiments. **, P < 0.01; ***, P < 0.001.