Curcumin exerts anti-inflammatory and vasoprotective effects through amelioration of NFAT-dependent endothelin-1 production in mice with acute Chagas cardiomyopathy

Abstract

BACKGROUND The anti-inflammatory and cardioprotective properties of curcumin (Cur), a natural polyphenolic flavonoid isolated from the rhizomes of Curcuma longa, are increasingly considered to have beneficial effects on the progression of Chagas heart disease, caused by the protozoan parasite Trypanosoma cruzi.OBJECTIVE To evaluate the effects of oral therapy with Cur on T. cruzi-mediated cardiovasculopathy in acutely infected mice and analyse the in vitro response of parasite-infected human microvascular endothelial cells treated with this phytochemical.METHODS Inflammation of heart vessels from Cur-treated and untreated infected mice were analysed by histology, with benznidazole (Bz) as the reference compound. Parasitaemia was monitored by the direct method. Capillary permeability was visualised by Evans-blue assay. Myocardial ET-1, IL-6, and TNF-α mRNA expressions were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Microvascular endothelial HMEC-1 cells were infected in vitro with or without addition of Cur or Bz. Induction of the Ca2+/NFAT pathway was assessed by fluorometry, immunoblotting, and reporter assay.FINDINGS Oral Cur therapy of recently infected mice reduced inflammatory cell infiltration of myocardial arteries without lowering parasite levels. Compared to that of the phosphate-buffered saline-receiving group, hearts from Cur-treated mice showed significantly decreased vessel inflammation scores (p < 0.001), vascular permeabilities (p < 0.001), and levels of IL-6/TNF-α (p < 0.01) and ET-1 (p < 0.05) mRNA. Moreover, Cur significantly (p < 0.05 for transcript; p < 0.01 for peptide) downregulated ET-1 secretion from infected HMEC-1 cells. Remarkably, Cur addition significantly (p < 0.05 at 27.0 μM) interfered with T. cruzi-dependent activation of the Ca2+/NFATc1 signalling pathway that promotes generation of inflammatory agents in HMEC-1 cells.CONCLUSIONS Oral treatment with Cur dampens cardiovasculopathy in acute Chagas mice. Cur impairs the Ca2+/NFATc1-regulated release of ET-1 from T. cruzi-infected vascular endothelium. These findings identify new perspectives for exploring the potential of Cur-based interventions to ameliorate Chagas heart disease.

Cardioprotective Activity of Selected Polyphenols Based on Epithelial and Aortic Cell Lines. A Review

“…Furthermore, the in vitro study showed that curcumin decreases the release of the vasoactive peptide, reduces [Ca 2+ ] i response, and prevents parasite-triggered NFATc1 nuclear translocation, leading to the cytoplasmic accumulation of NFATc1 protein ( Figure 1 ). This suggests that curcumin possesses cardioprotective activity and may abolish the [Ca 2+ ] i -associated activation of the NFATc1 isoform in vascular endothelial cells infected by Trypanosoma cruzi [ 24 ].…”

Comparing the preventive effect of sodium hydrosulfide, leptin, and curcumin against L-arginine induced acute pancreatitis in rats: role of corticosterone and inducible nitric oxide synthase

“…There is much controversy about the effect of H 2 S, leptin and curcumin in inflammatory condi-tions. Some studies have shown that they may have pro-inflammatory effects (Ang et al 2013;Singh et al 2014; Pham and Mathis 2017), while, others have proved the anti-inflammatory effects of them (Qi et al 2017;Ali et al 2018;Hernandez et al 2018).…”

Current trends in the pharmacological management of Chagas disease

“…Vasconcelo et al, 2017N,N dimethylsphingosin (Sphingosine kinase inhibitor)C57BL/6 miceReduction of cardiac inflammation, fibrosis and galectin-3 expression, modulation of inflammatory mediators such as IFNγ and TNFα, improvement in exercise capacity, but without improving cardiac electrical disturbances.Montenote et al, 2017 M. nigra (Phytotherapeutic compound)Swiss miceDecreased parasitemia, and may be the subject of further research for a greater analysis of the mechanisms of action and bioavailability.Horta et al, 2017Carvedilol (Adrenergic Blocker)C57BL/6 miceFor this experimental model, carvedilol therapy was not able to alter levels of circulating parasites, but modulates the pattern of mediators of CCL2 and IL-10 when the VL10 strain of T. cruzi. Reigada et al, 2017Isotretinoin (Antiacne)CHO–K1 cellsIsotretinoin inhibited polyamine transport, also showed strong inhibition of the explanted trypomastigote of infected cells but being significantly less effective at the epimastigote stage.Hernández et al (2018)Curcumin (cholagogue, anti-inflammatory)Human microvascular endothelial cells, C57BL/6 miceReduced inflammatory cell infiltration without lowering parasitemia.Ferreira et al (2018)Sertraline (Antidepressant)In silico studies, Balb/c mice E fficacy against intracellular amastigotes and bloodstream trypomastigotes, with low cytotoxicity to mammalian cellsFracasso et al, 2018Resveratrol (antioxidant/cardioprotective)Swiss miceCan be use for the treatment of neuroinflammation or neuroprotection during Chagas disease, improving gliogenesis and restoring neural migration.Simões-Silva et al (2019)Imatinib (Antineoplastic Agent Immunological Agent)Mouse fibroblastsThe drug was moderately active against the parasite, with low selectivity indexND* not determined.…”

“…Furthermore, resveratrol acts as a neuroprotector during CD, improving gliogenesis and neural migration (Fracasso et al, 2019). Curcumin, a herbal supplement and a natural food coloring extracted from ginger, is a natural phenol that failed in reducing parasitemia, although lowering inflammatory leukocyte infiltration (Hernández et al, 2018).…”