Chemotherapeutic Efficacy of Phosphodiesterase Inhibitors in Chagasic Cardiomyopathy

• Mice infected with T. cruzi control acute parasitemia but develop chronic chagasic cardiomyopathy.
• Treatment with SIL (a phosphodiesterase inhibitor) during a therapeutic window of indeterminate phase provided powerful cardioprotective effects against chronic development of cardiomyopathy and LV dysfunction.
• SIL normalized the cGMP-dependent protein kinase activity and mitochondrial oxidative metabolism, and established the oxidant/antioxidant balance in chagasic myocardium.
• SIL prevented the oxidative/inflammatory adducts that precipitate cardiomyocytes death and cardiac remodeling in CCM.

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

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