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Selective decrease of components of the creatine kinase system and ATP synthase complex in chronic Chagas disease
Priscila Camillo Teixeira1, Ronaldo Honorato Barros Santos, Alfredo Inácio Fiorelli
1Laboratory of Immunology, Heart Institute, School of Medicine, University of São Paulo, São Paulo, Brazil.
Insights
Chronic Chagas disease cardiomyopathy (CCC) shows reduced levels of key enzymes for ATP production, indicating a more severe energy deficit compared to other cardiomyopathies. This impairment may explain the loss of contractile function in CCC patients.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory condition with a poor prognosis.
- Heart failure in CCC is linked to impaired myocardial energy metabolism and contractile dysfunction.
- Trypanosoma cruzi infection causes CCC, prevalent in Latin America.
Purpose of the Study:
- To investigate myocardial gene and protein expression of key ATP-producing mitochondrial enzymes.
- To assess enzyme activity in end-stage CCC, idiopathic dilated cardiomyopathy (IDC), and ischemic cardiomyopathy (IC).
- To correlate metabolic changes with contractile dysfunction in CCC.
Main Methods:
- Analysis of myocardial samples from CCC, IC, IDC patients, and heart donors.
- Quantification of mitochondrial creatine kinase (CKMit), muscular creatine kinase (CKM), and ATP synthase subunits (alpha, beta) using immunoblotting and real-time RT-PCR.
- Assessment of total myocardial creatine kinase (CK) activity.
Main Results:
- CKM protein levels and CK activity were reduced across all cardiomyopathy groups.
- ATP synthase alpha chain protein levels and total CK activity were significantly lower in CCC compared to IC and IDC.
- CCC myocardium exhibited a selective reduction in enzymes vital for cytoplasmic ATP maintenance.
Conclusions:
- Selective impairment of the creatine kinase (CK) system in CCC may contribute to reduced inotropic reserve.
- Lower ATP synthase alpha levels suggest decreased ATP generation via oxidative phosphorylation in CCC.
- CCC patients exhibit a more pronounced myocardial energetic deficit than other dilated cardiomyopathies.
Background:
Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory dilated cardiomyopathy with a worse prognosis than other cardiomyopathies. CCC occurs in 30 % of individuals infected with Trypanosoma cruzi, endemic in Latin America. Heart failure is associated with impaired energy metabolism, which may be correlated to contractile dysfunction. We thus analyzed the myocardial gene and protein expression, as well as activity, of key mitochondrial enzymes related to ATP production, in myocardial samples of end-stage CCC, idiopathic dilated (IDC) and ischemic (IC) cardiomyopathies.
Methodology/Principal Findings:
Myocardium homogenates from CCC (N=5), IC (N=5) and IDC (N=5) patients, as well as from heart donors (N=5) were analyzed for protein and mRNA expression of mitochondrial creatine kinase (CKMit) and muscular creatine kinase (CKM) and ATP synthase subunits aplha and beta by immunoblotting and by real-time RT-PCR. Total myocardial CK activity was also assessed. Protein levels of CKM and CK activity were reduced in all three cardiomyopathy groups. However, total CK activity, as well as ATP synthase alpha chain protein levels, were significantly lower in CCC samples than IC and IDC samples. CCC myocardium displayed selective reduction of protein levels and activity of enzymes crucial for maintaining cytoplasmic ATP levels.
Conclusions/Significance:
The selective impairment of the CK system may be associated to the loss of inotropic reserve observed in CCC. Reduction of ATP synthase alpha levels is consistent with a decrease in myocardial ATP generation through oxidative phosphorylation. Together, these results suggest that the energetic deficit is more intense in the myocardium of CCC patients than in the other tested dilated cardiomyopathies.
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