Chemotherapeutic Efficacy of Phosphodiesterase Inhibitors in Chagasic Cardiomyopathy

• DOI: 10.1016/j.jacbts.2016.04.005
• Publication Date: 2016-06-11T13:46:14Z
• Authors: Jian-jun Wen; Xianxiu Wan; John Thacker; Nisha Jain Garg
• Keywords: Chagas Disease; Cardiotoxicity

Molecular mechanisms of Trypanosoma cruzi (Tc)-induced Chagasic cardiomyopathy (CCM) are not well understood. The NO-cGMP-PKG1α pathway maintains cardiac homeostasis and inotropy may be disturbed due to phosphodiesterase (PDE5)-mediated cGMP catabolism in CCM. To test this, C57BL/6 mice were infected with T. cruzi, after the control acute parasitemia (∼45 days post-infection), given sildenafil (SIL) (1 mg/kg) treatment for 3 weeks that ended long before chronic disease phase (∼150 post-infection). PDE5 was increased cGMP/PKG activity decreased chagasic myocardium. Transthoracic echocardiography revealed left ventricular (LV) systolic function, is, stroke volume, output, ejection fraction, significantly mice. SIL resulted normal levels preserved LV function. cardioprotective effects provided through inhibition collagenosis inflammation otherwise pronounced Further, restored mitochondrial DNA–encoded gene expression, complex I–dependent (but II–dependent) ADP-coupled respiration, oxidant/antioxidant balance In vitro studies cardiomyocytes verified conserved redox metabolic state cellular health via maintaining antioxidant status compromised response infection. We conclude therapy useful controlling dysfunction pathology