Abstract 14936: Activation of Cardiomyocyte Proliferation via Targeting Mir-128 in Infarcted Heart
Background: In contrast to neonatal hearts, adult mouse cardiac regeneration ability is limited due to the ineffective reactivation of cardiomyocyte (CM) proliferation following injury. However, it is unclear whether the underlying mechanism employed during the neonatal period can be manipulated in the adult heart to activate endogenous CM proliferation and facilitate cardiac regeneration.
Methods and Results: Mouse hearts were harvested at postnatal days 1, 7, and 28 (P1, P7, and P28) and analyzed to screen the miRNA involved in postnatal CM proliferation. The percentage of proliferative CM (Ki67+) in mouse hearts was significantly decreased between P7 and P28, whereas expression of miR128 progressively increased. Gain- and loss-of-function approaches using genetic mouse models were then developed to delineate the functional effects and mechanisms that involved in miR128-regulated CM proliferation. Cell dedifferentiation, DNA synthesis, mitosis, and cytokinesis were analyzed by immunostaining. Cell cycle associated protein expression was analyzed by Western blotting. In mice, overexpression of miR128 led to decreased CM proliferation. In contrast, deletion of miR128 (iKO) induced a significant increase in CM proliferation (as quantified by increased Edu+ CM population). Moreover, CDK inhibitor (p27) transcription was epigenetically silenced by miR128 deletion through targeting SUZ12 in hearts, leading to the activation of positive cell cycle regulators (Cyclin E and CDK2). Finally, postnatal deletion of miR128 was sufficient to induce CM reentry into the cell cycle leading to reduced fibrosis, improved post-injury remodeling, and heart function recovery following myocardial infarction in adult mice (Fig. 1).
Conclusion: These results demonstrate miR128 is a critical regulator of postnatal CM proliferation, and could provide a promising therapeutic option for heart repair after injury.
Author Disclosures: W. Huang: None. J. Liang: None. L. Jiang: None. W. Cai: None. P. Christian: None. M. Xu: None. Y. Wang: None.
- © 2016 by American Heart Association, Inc.