Abstract 3025: MicroRNA-378, Which Exists Intronic Lesion of PGC-1beta, Deteriorate Cardiomyocyte Survival Under Oxidative Stress
Background: MicroRNAs are 19 –25 nucleotide, small non-coding RNAs that regulate gene expression through translational repression by base pairing with 3′ untranslated region (3′UTR) of specific messenger RNA (mRNA). Growing evidences indicate that microRNAs are associated with physiological processes such as cell growth and differentiation. However, their functions under pathological condition remain unknown.
Methods and Results: In order to study the role of miRNAs in the cardiovascular disease, we first examined the expression profile of microRNAs in a mouse model of myocardial infarction. C57BL/6 mice were sacrificed at 24hours after coronary ligation and we performed microRNA array analysis of the RNA prepared from the infracted and non-infarcted region. We then specifically analyzed miRNAs which are located within the intronic region of the genes with already known function. We found that microRNA-378 (miR-378), which is located in the intronic region of PGC-1β (Peroxisome proliferator activated receptor gamma coactivator-1β) gene and is expressed abundantly in the heart, was decreased in infarcted region compared with non-infarcted region (0.50 folds, four specimens were mixed). As expected, mRNA level of PGC-1β was also repressed in infracted region (0.17 folds, four specimens were mixed). To investigate whether the reduction of miR-378 in infarcted region is adaptation or maladaptation, miR-378 was overexpressed in rat neonate ventricular myocytes using lenti-viral system. MiR-378 decreased intracellular ATP (53.0±10.5 % decreased, p<0.005, n=4) and reduced the survival rate (58.0±1.40 vs 38.2±3.15 %, p<0.05, n=4) after stimulation with 50uM hydrogen peroxide for 12 hours. Furthermore, we found that the activation of Akt was decreased after stimulation with hydrogen peroxide, when miR-378 was overexpressed in cardiomyocytes. Since the overexpression of PGC-1β auguments the oxidative stress in the heart, these data suggest that decreased miR-378 expression as long as the reduced expression of PGC-1β is beneficial under oxidative stress in the heart.
Conclusions: MicroRNA-378 is a therapeutic target for the reduction of myocardial injury by oxidative stress in myocardial infarction.