Abstract
Mammalian cardiac Purkinje fibers (PFs) are specified from ventricular trabecular myocardium during mid-gestation and undergo limited proliferation before assuming their final form. MicroRNA-1 (miR-1), a negative regulator of proliferation, is normally expressed in the heart at low levels during the period of PF specification and outgrowth, but expression rises steeply after birth, when myocardial proliferation slows and postnatal cardiac maturation and growth commence. Here, we test whether premature up-regulation and overexpression of miR-1 during the period of PF morphogenesis influences PF development and function. Using a mouse model in which miR-1 is expressed under the control of the Myh6 promoter, we demonstrate that premature miR-1 expression leads to PF hypoplasia that persists into adulthood, and miR-1 TG mice exhibit delayed conduction through the ventricular myocardium beginning at neonatal stages. In addition, miR-1 transgenic embryos showed reduced proliferation within the trabecular myocardium and embryonic ventricular conduction system (VCS), a source of progenitor cells for the PF. This repression of proliferation may be mediated by direct translational inhibition by miR-1 of the cyclin dependent kinase Cdk6, a key regulator of embryonic myocardial proliferation. Our results suggest that altering the timing of miR-1 expression can regulate PF development, findings which have implications for our understanding of conduction system development and disease in humans.
Highlights
The cardiac ventricular conduction system (VCS) is a multicomponent functional unit composed of specialized cardiomyocytes that transmit electrical impulses from the atrial to the ventricular myocardium
We found that while RR and PR intervals were not changed between miR-1 TG neonates and their littermates, the QRS interval was significantly increased in the miR-1 TG mice (p < 0.05), demonstrating isolated dysfunction of the VCS in hearts with Purkinje fibers (PF) hypoplasia and dysregulation of gene expression (Figures 3D,E)
We have used a transgenic mouse line with miR1 overexpression under the control of the Myh6 promoter to define the impact of increased embryonic miR-1 dosage on structure and function of the VCS
Summary
The cardiac ventricular conduction system (VCS) is a multicomponent functional unit composed of specialized cardiomyocytes that transmit electrical impulses from the atrial to the ventricular myocardium. The bundle branches ramify into conduction fascicles, Abbreviations: PF, Purkinje fiber; miR-1, microRNA-1; VCS, ventricular conduction system. MicroRNA-1 Regulates Purkinje Fiber Development which, in turn, arborize into a finely branched network of specialized cardiomyocytes known as Purkinje fibers (PF). At their distal ends, PFs directly activate working cardiomyocytes, leading to mechanically synchronous ventricular contraction. Malfunction and/or malformation of the Purkinje network can lead to conduction delay, dyssynchronous contraction, and tachyarrhythmias, and are important sources of morbidity in patients with congenital and acquired heart disease (Boyden et al, 2016)
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