Abstract 869: Upregulation Of Mir-451: Singularly Demarcates The Onset Of Heart Failure In Mice, And Targets Titin
MicroRNA (miRNA) are ~22 ribonucleotides-long, with a potential to recognize multiple mRNA targets guided by sequence complimentarity. This class of molecules is functionally versatile, with the capacity to specifically inhibit translation, as well as, induce mRNA degradation, through targeting the 3′-untranslated regions. The levels of individual miRNA vary under different developmental, biological, or pathological conditions, thus, implicating them in normal and pathological cellular attributes. We have previously reported a distinct miRNA pattern, distinguishing pressure-overload compensatory hypertrophy, which was a recapitulation of the neonatal pattern. In this study, we hypothesized that further deregulation of specific miRNA expression will distinguish the decompensated phase of hypertrophy. To test this, we used microarray analysis on RNA samples isolated from hearts subjected to transaortic constriction (TAC) or a sham operation for 2.5, 3, and 3.5 weeks (n=3, each). The onset of heart failure, in our model, coincides with 3 wk of TAC, as monitored by echocardiography and haemodynamic parameters. Overall the miRNA expression pattern in the 3 time points resembled the pattern previously reported during compensatory hypertrophy except for one distinct miRNA, miR-451. MiR-451 was increased 3.5 Â± 1 and 4.5 Â± 1.2 folds, at 3 and 3.5 wks, respectively, as confirmed by Northern blotting. The expression pattern differs from other hypertrophy-associated miRNA, where it is high in the adult vs. neonatal heart and increases further with the onset of failure, thus suggesting an adverse function. To identify the functional role of miR-451 in cardiac myocytes, we cloned the premature miR-451 stem-loop into a recombinant adenovirus. Computational programs such as TargetScanS, has identified titin as a potential target for miR-451. Failing hearts are characterized by a downregulation in titin, causing sarcomeric breakdown and structural deterioration. Thus, we propose that upregulation of miR-451 singularly demarcates the onset of decompensation in a pressure overload mouse model. This results in downregulation of titin, which underlies the mechanism of contractile dysfunction during heart failure.