Decreased Myocardial Expression of Dystrophin and Titin mRNA and Protein in Dilated Cardiomyopathy: Possibly an Adverse Effect of TNF-α
- 273 Downloads
Background and aims
While the molecular basis of dilated cardiomyopathy (DCM) remains uncertain, concrete evidence is emerging that sarcomeric and cytoskeleton gene expression of myocardium isolated from failing versus non-failing patients differ dramatically. The central aim to this work was to find out the possible role of dystrophin and titin along with the TNF-α in the pathogenesis of cardiomyopathy.
Patients and methods
mRNA levels and protein expression of a cytoskeletal protein, dystrophin and a sarcomeric protein, titin in endomyocardial biopsies of DCM patients were examined using RT-PCR and immunohistochemistry, respectively. Further, we examined the effect of TNF-α on myocardial expression of titin and dystrophin in vitro in rat cardiac myoblast cell line (H9c2).
We observed significantly decreased mRNA and protein levels of dystrophin and titin in endomyocardial biopsy of DCM patients as compared to control group. The decreased levels of these proteins correlated with the severity of the disease. Plasma levels of both TNF-α and its soluble receptors TNFR1 and TNFR2 were found to be significantly higher in patients as compared to control group. Treatment of H9c2 cells with TNF-α resulted in a dose- and time-dependent decrease in mRNA levels of dystrophin and titin. Pretreatment of these cells with MG132, an inhibitor of nuclear factor kappa B (NF-κB) pathway, abolished TNF-α-induced reduction in mRNA levels of dystrophin and titin.
Our results suggest that reduced expression of dystrophin and titin is associated with the pathophysiology of DCM, and TNF-α may modulate the expression of these proteins via NF-κB pathway.
KeywordsDilated cardiomyopathy endomyocardial biopsy dystrophin titin-mRNA expression proinflammatory cytokines
chronic heart failure
tumor necrosis factor-alpha
tumor necrosis factor receptor
nuclear factor kappa B
atrial septal defect
ventricular septal defect
left ventricular ejection fraction
left ventricular end diastolic
New York Heart Association
The present study was supported by the Indian council of Medical Research, New Delhi, India and Postgraduate Institute of Medical Education and Research.
- 7.Vatta M, Stetson SJ, Jimenez S, Entman ML, Noon GP, Bowles NE, et al. Molecular normalization of dystrophin in the failing left and right ventricle of patients treated with either pulsatile or continuous flow-type ventricular assist devices. J Am Coll Cardiol. 2004;43:811–7.CrossRefPubMedGoogle Scholar
- 12.Ahmad S, Otaal PS, Rai TS, Bahl A, Saikia UN, Manoj RK, et al. Circulating proinflammatory cytokines and N-terminal pro-brain natriuretic peptide significantly decrease with recovery of left ventricular function in patients with dilated cardiomyopathy. Mol Cell Biochem. 2009;324:139–45.CrossRefPubMedGoogle Scholar