Abstract 2573: MicroRNA-133a Differentially Regulates the Expression and the Remodeling of Ventricular Transient Outward K+ Currents (Ito)
Background: Expression of the muscle specific microRNA, miR-133a, has been linked to the regulation of pressure overload induced left ventricular hypertrophy (LVH), and to the remodeling of HCN-encoded pacemaker and ERG-encoded delayed rectifier K+ channels in hypertrophy and diabetes. Pronounced alterations in fast transient outward K+ current, Ito,f, densities and action potential durations are routinely observed in hypertrophied and failing hearts, as well as in diabetes, suggesting that Ito,f may also be a critical target of miR-133a.
Methods and Results: To explore this hypothesis directly, electrophysiological experiments were completed on (αMHC-miR-133a) animals expressing miR-133a in the adult heart driven by the αMHC promoter. Surface ECG recordings revealed marked QTc prolongation in αMHC-miR-133a (47.5±1.1 ms) transgenic, compared with non-transgenic (ntg) (43.6±1.1ms), littermates. Action potentials recorded from left ventricular (LV) myocytes were significantly (P<0.02) longer in αMHC-miR-133a, than ntg, cells. In voltage-clamp recordings, peak voltage-gated outward K+ (Kv) current densities were significantly (P<0.001) lower in αMHC-miR-133a LV cells. Analyses of the Kv current waveforms revealed that Ito,f densities were significantly (P<0.001) lower, whereas delayed rectifier Kv (IK,slow and Iss) current densities were similar in αMHC-miR-133a and ntg LV cells. In addition, the remodeling of Ito,f was more pronounced in endocardial than in epicardial LV cells, partially collapsing the normal transmural gradient of Ito,f. As previously demonstrated, action potential durations and Kv current (Ito,f, IK,slow and Iss) densities were reduced significantly (P<0.001) in ntg LV myocytes from animals 1 week following transverse aortic constriction (TAC) induced LVH. Although similar decreases in IK,slow and Iss densities were observed, Ito,f remodeling was not evident in αMHC-miR-133a LV myocytes with TAC.
Conclusion: Taken together, these results reveal a role for miRNA-133a in regulating the functional cell surface expression of cardiac Ito,f channels and suggest that miR-133a might be a potential target to attenuate or reverse Ito,f remodeling in the hypertrophied or failing heart.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).