Chemotherapeutic Efficacy of Phosphodiesterase Inhibitors in Chagasic Cardiomyopathy

Jian jun Wen, Xianxiu Wan, John Thacker, Nisha Garg

Research output: Contribution to journalReview article

8 Citations (Scopus)

Abstract

Molecular 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.

Original languageEnglish (US)
Pages (from-to)235-250
Number of pages16
JournalJACC: Basic to Translational Science
Volume1
Issue number4
DOIs
StatePublished - Jun 1 2016

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Phosphodiesterase Inhibitors
Cardiomyopathies
Trypanosoma cruzi
Left Ventricular Function
Myocardium
Antioxidants
Infection
Type 5 Cyclic Nucleotide Phosphodiesterases
Mitochondrial Genes
Parasitemia
Left Ventricular Dysfunction
Inbred C57BL Mouse
Cardiac Myocytes
Oxidants
Cardiac Output
Stroke Volume
Adenosine Diphosphate
Oxidation-Reduction
Echocardiography
Sildenafil Citrate

Keywords

  • antioxidant/oxidant balance
  • chagasic cardiomyopathy
  • chronic inflammation
  • LV function
  • mitochondrial respiration
  • sildenafil
  • Trypanosoma cruzi

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Chemotherapeutic Efficacy of Phosphodiesterase Inhibitors in Chagasic Cardiomyopathy. / Wen, Jian jun; Wan, Xianxiu; Thacker, John; Garg, Nisha.

In: JACC: Basic to Translational Science, Vol. 1, No. 4, 01.06.2016, p. 235-250.

Research output: Contribution to journalReview article

Wen, Jian jun ; Wan, Xianxiu ; Thacker, John ; Garg, Nisha. / Chemotherapeutic Efficacy of Phosphodiesterase Inhibitors in Chagasic Cardiomyopathy. In: JACC: Basic to Translational Science. 2016 ; Vol. 1, No. 4. pp. 235-250.
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