Modulation of the p38MAPK pathway in failing human myocardium secondary to rheumatic heart disease.

BACKGROUND AND AIM OF THE STUDY: It is well established that rheumatic heart disease can induce congestive heart failure, a condition in which the heart is unable to pump out all of its blood content. It was hypothesized that modulation of the p38MAPK signal and cardiomyocyte apoptosis may result in an aggravation of heart failure secondary to rheumatic heart disease.

METHODS

Ventricular tissues were collected from healthy (control) subjects and from patients diagnosed with rheumatic heart disease and symptomatic heart failure in NYHA functional classes II to IV. Apoptosis was monitored using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. The protein expression of p38MAPK, p-p38MAPK and, MKP-1 were determined with Western blotting, and P38MAPK activation with an immunoprecipitation-kinase assay.

RESULTS

Compared to controls, TUNEL-positive cells were significantly higher in heart failure patients in relation to NYHA class (0.33 +/- 0.53% versus 7.38 +/- 3.51%, 11.85 +/- 3.72% and 19.86 +/- 4.94% in classes II, II and IV, respectively). In class II, p38MAPK activity was markedly activated and MKP-1 depressed. In classes III and IV, p38MAPK, p38MAPK activity and p-p38MAPK remained significantly elevated, while MKP-1 was decreased. Moreover, p38MAPK and p-p38MAPK activities in classes III and IV were higher than in class II. With progression of heart function, MKP-1 was clearly depressed, while p38MAPK activity was elevated in class IV patients compared to those in classes II and III.

CONCLUSION

The study results show that mechanical overloading of the failing human heart secondary to rheumatic heart disease results in a differential regulation of the MAPK activity pathway, and a corresponding increase in apoptosis.