Apoptosis de los cardiomiocitos en pacientes con estenosis aórtica severa. Posible implicación de los microRNAs

Zusammenfassung

Rationale: Cardiomyocyte apoptosis may have an impact on the myocardium of patients with severe aortic stenosis (AS). MicroRNAs may be involved in this process. Material & methods: 28 endomyocardial biopsies from AS patients were used. Cardiomyocyte apoptotic index (CMAI) was assessed by TUNEL. Bax, Bcl-2 and BNIP3 were determined by western blot. Cardiomyocyte and cardiac progenitor cells (CPC) density were quantified histologically. MicroRNA expression was studied in 5 patients from each subgroup by TLDA, validating those of interest by real-time RT-PCR in the whole population. Results: Two subgroups of patients were identified according to the CMAI: subgroup1 (CMAI≤0.08%, [n=16]) and subgroup2 (CMAI>0.08%, [n=12]). This distribution was verified by higher Bax/Bcl-2 and BNIP3/Bcl-2 ratios in subgroup2 patients. These patients showed lower cardiomyocyte density and ejection fraction, and higher prevalence of heart failure and NT-proBNP levels than subgroup1 patients. Additionally, CPC density was increased in subgroup2 patients. CMAI was inversely associated with cardiomyocyte density and ejection fraction and directly associated with CPC density and NT-proBNP. 70 microRNAs were significantly altered more than 4-fold in subgroup2 patients compared with subgroup1. MiR-10b and miR-338-3p down-regulation, and miR-198 up-regulation in subgroup2 patients, and their association with the CMAI were validated. MiR-10b inhibition in murine cardiomyocytes increased their susceptibility to apoptosis in baseline conditions and in the presence of staurosporine. Conclusion: Cardiomyocyte apoptosis is increased in AS, namely in a subgroup of patients, and is associated with diminished cardiomyocyte density and heart failure. MiR-10b down-regulation is involved in this process, emerging as a potential therapeutic target.