Role of micro RNAs in obesity-mediated premature cardiac ageing in patients

Background: Obesity results in signs of increased oxidative stress, pro-apoptotic activation, impaired mitochondrial biogenesis and function in cardiomyocytes and disturbances in whole-body glucose metabolism and adipocytokine release in young obese patients. These disturbances resemble many of the changes otherwise observed in older patients, suggesting a prematurely aged phenotype in young obese patients. MicroRNAs are small noncoding RNAs that posttranscriptionally control gene expression. They have emerged as diagnostic tools and are currently investigated as novel therapeutic options to preserve cardiac function. Here, we investigated the effect of obesity on expressional patterns of micro RNAs (miRNAs) in right atrial (RA) tissue of patients. These data were compared with data obtained from the RA of rats undergoing caloric restriction (CR, -40%) in order to identify micro RNAs mutually regulated by CR or obesity.

Methods: We obtained samples from the right atrium (RA) of male young (50.2 ± 5.2 years) and normosome/obese (BMI 24.0 ± 1.1 / BMI 33.8 ± 4.3) patients undergoing cardiac surgery and male rats undergoing CR (6 months, -40%). The screens for differentially expressed micro RNA's was performed with miRCURY LNA™ microRNA Arrays (Exiqon) and confirmed by real-time PCR. Target gene prediction was performed by three independent online tools and confirmed with luciferase reporter gene assays and Western blotting.

Results: Obesity resulted in the differential expression of 31 miRNAs in human RAs, while altered the expression of 24 miRNAs. Among these miRNAs, 8 miRNAs (let7a, let7c, miR143, miR23a, miR26a, miR26b, miR29a and miR-292-5p) were mutually regulated by obesity and by CR. The differential expression of many of these miRNAs could be confirmed by qPCR in RA tissue from patients and rats. Among the consistent target genes of these differentially expressed miRs were genes involved in cardioprotection and in ageing processes such as PGC-1alpha, SIRT3 and IGF1. Theses target genes were confirmed by reporter gene analyses and Western blotting. First functional analyses suggest an influence of the differentially expressed miRNAs on cell viability and apoptosis in vitro.

Conclusion: Differential expression of miRNAs is induced by obesity in RA tissue of young patients and may contribute to the prematurely aged phenotype of cardiomyocytes.