title: Chemotherapeutic efficacy of phosphodiesterase inhibitors in chagasic cardiomyopathy.
abstract: BACKGROUND
  Chagasic cardiomyopathy (CCM) caused byTrypanosoma cruzi(Tc) infection is prevalent in Latin America and recognized as an emerging infectious heart disease in the US. The NO-cGMP-PKG1α pathway maintains cardiac homeostasis and inotropy and may be disturbed due to phosphodiesterase (PDE5) mediated cGMP catabolism in CCM.
  
  
  RESULTS
  C57BL/6 mice were infected withTc, and at the end of acute parasitemia (i.e. 45 days post-infection), treated with sildenafil (SIL, 1 mg/kg) twice per week for 3 weeks. Mice were monitored at 150 days post-infection corresponding to chronic disease phase. The cGMP/PKG activity was decreased by 2-fold and PDE5 expression was increased by 1.4-fold and 100% at RNA and protein levels, respectively, in chagasic myocardium. Transthoracic echocardiography showed the left ventricular (LV) systolic function, i.e., stroke volume, cardiac output, and ejection fraction, were significantly decreased in chagasic mice. Sildenafil treatment resulted in normal levels of PDE5 and cGMP/PKG activity and preserved the LV function in chagasic mice. The cardioprotective effects of SIL were provided through inhibition of cardiac collagenosis and chronic inflammation that otherwise were pronounced in CCM. Further, mtDNA-encoded gene expression and ADP-coupled mitochondrial respiration were decreased and mitochondrial oxidative stress and cellular oxidative damage (lipid hydroperoxides and protein carbonyls) were increased in chagasic myocardium. SIL treatment restored the mtDNA-encoded gene expression and complex I (but not complex II) dependent ADP-coupled respiration, and established the oxidant/antioxidant balance in chagasic myocardium.In vitrostudies in cardiomyocytes verified that SIL conserved the redox metabolic state and cellular health via maintaining the antioxidant status that otherwise was compromised in response toTcinfection.
  
  
  CONCLUSIONS
  SIL therapy was useful in controlling the LV dysfunction and chronic pathology in CCM.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Wen
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas.
authors.forename: Xianxiu
authors.initials: X
authors.lastname: Wan
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas.
authors.forename: John
authors.initials: J
authors.lastname: Thacker
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas; Department of Pathology, UTMB, Galveston, TX; Institute for Human Infections and Immunity, UTMB, Galveston, TX.
authors.forename: Nisha Jain
authors.initials: NJ
authors.lastname: Garg
keywords: Chagasic cardiomyopathy; LV function; Sildenafil; Trypanosoma cruzi; antioxidant/oxidant balance; chronic inflammation; mitochondrial respiration