title: Cardioprotective actions of curcumin on the pathogenic NFAT/COX-2/prostaglandin E2pathway induced during Trypanosoma cruzi infection.
abstract: BACKGROUND
  Diverse cardiovascular signaling routes have been considered critical for Chagas cardiomyopathy caused by the protozoan parasite Trypanosoma cruzi. Along this line, T. cruzi infection and endothelin-1 (ET-1) have been shown to cooperatively activate the Ca2+/NFAT cascade in cardiomyocytes, leading to cyclooxygenase type 2 (COX-2) induction and increased release of prostanoids and prohypertrophic peptides.
  
  
  OBJECTIVE
  To determine whether the well-known cardioprotective and anti-inflammatory effects of curcumin (Cur) could be helpful to interfere with this key machinery for pathogenesis of Chagas myocarditis.
  
  
  METHODS
  Cur treatment was evaluated through in vivo studies using a murine model of acute T. cruzi infection and in vitro experiments using ET-1-stimulated and parasite-infected mouse cardiomyocytes.
  
  
  METHODS
  Cur-treated and untreated infected mice were followed-up to estimate survival postinfection and heart tissues from both groups were analyzed for inflammatory infiltration by histopathology, whereas parasite load, induction of arachidonic acid pathway and natriuretic peptide expression were determined by real-time PCR. Molecular analysis of Cur myocardial targets included intracellular calcium measurement, NFAT and COX-2 induction in transfected cells, and assessment of NFAT, COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) levels by immunoblotting, prostaglandin E2(PGE2) by ELISA, b-type natriuretic peptide (BNP) by real-time PCR, and PGE2/EP4 receptor/BNP interaction by transwell experiments.
  
  
  RESULTS
  Cur treatment of acute Chagas mice enhanced survival and proved to hinder relevant inflammatory processes in the heart, including leukocyte recruitment, activation of the eicosanoid pathway and BNP overexpression, without modifying parasite burden in the organ. Cur was capable of blocking Ca2+-dependent NFATc1 transcriptional activity, COX-2 and mPGES-1 induction, and subsequent PGE2production in ET-1-stimulated and parasite-infected cardiomyocytes. Furthermore, the decline of cardiomyocyte-derived prostaglandin levels achieved upon Cur treatment impaired effective PGE2/EP4 receptor interaction, resulting in attenuated expression of BNP, a strong indicator of cardiac pathogenesis in Chagas disease, in both infected and uninfected cells.
  
  
  CONCLUSIONS
  Our current study shows a putative mechanism of action of Cur involving inhibition of the Ca2+/NFAT-dependent, pathogenic COX-2/mPGES-1/PGE2pathway in T. cruzi-infected myocytes, underlying cardioprotection achieved in Cur-treated infected mice. With a view to the limited therapeutic possibilities available, Cur represents a promising approach for the treatment of Chagas heart disease.
authors.affiliation: Laboratorio de Biomedicina Molecular, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina.
authors.forename: Matías
authors.initials: M
authors.lastname: Hernández
authors.affiliation: Laboratorio de Biomedicina Molecular, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina.
authors.forename: Susana
authors.initials: S
authors.lastname: Wicz
authors.affiliation: Servicio de Parasitología-Chagas, Hospital de Niños "Dr. Ricardo Gutiérrez", Ciudad de Buenos Aires, Argentina. Electronic address: ricardocorral56@hotmail.com.
authors.forename: Ricardo S
authors.initials: RS
authors.lastname: Corral
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002598:Chagas Cardiomyopathy / Q000188:drug therapy / Q000378:metabolism* / Q000469:parasitology; D014355:Chagas Disease; D030024:Curcuma / Q000737:chemistry; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D014349:Trypanosoma cruzi / Q000472:pathogenicity*
chemical_list: D000893:Anti-Inflammatory Agents; D019332:Endothelin-1; D050778:NFATC Transcription Factors; C467907:Nfatc4 protein, mouse; D010936:Plant Extracts; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003474:Curcumin; D015232:Dinoprostone
keywords: Cardiomyocyte; Curcumin; Cyclooxygenase type 2; Prostaglandin E(2); Trypanosoma cruzi; b-type natriuretic peptide