Abstract

ObjectivesNeuregulin 1 signaling plays an important role in cardiac trabecular development, and in sustaining functional integrity in adult hearts. Treatment with neuregulin 1 enhances adult cardiomyocyte differentiation, survival and/or function in vitro and in vivo. It has also been suggested that recombinant neuregulin 1β1 (NRG1β1) induces cardiomyocyte proliferation in normal and injured adult hearts. Here we further explore the impact of neuregulin 1 signaling on adult cardiomyocyte cell cycle activity.Methods and ResultsAdult mice were subjected to 9 consecutive daily injections of recombinant NRG1β1 or vehicle, and cardiomyocyte DNA synthesis was quantitated via bromodeoxyuridine (BrdU) incorporation, which was delivered using mini-osmotic pumps over the entire duration of NRG1β1 treatment. NRG1β1 treatment inhibited baseline rates of cardiomyocyte DNA synthesis in normal mice (cardiomyocyte labelling index: 0.019±0.005% vs. 0.003±0.001%, saline vs. NRG1β1, P<0.05). Acute NRG1β1 treatment did result in activation of Erk1/2 and cardiac myosin regulatory light chain (down-stream mediators of neuregulin signalling), as well as activation of DNA synthesis in non-cardiomyocytes, validating the biological activity of the recombinant protein. In other studies, mice were subjected to permanent coronary artery occlusion, and cardiomyocyte DNA synthesis was monitored via tritiated thymidine incorporation which was delivered as a single injection 7 days post-infarction. Daily NRG1β1 treatment had no impact on cardiomyocyte DNA synthesis in the infarcted myocardium (cardiomyocyte labelling index: 0.039±0.011% vs. 0.027±0.021%, saline vs. NRG1β1, P>0.05).SummaryThese data indicate that NRG1β1 treatment does not increase cardiomyocyte DNA synthesis (and consequently does not increase the rate of cardiomyocyte renewal) in normal or infarcted adult mouse hearts. Thus, any improvement in cardiac structure and function observed following neuregulin treatment of injured hearts likely occurs independently of overt myocardial regeneration.

Highlights

  • Many forms of cardiovascular disease are associated with acute or chronic cardiomyocyte loss

  • Ablation of the Neuregulin 1 gene [7, 8], the neuregulin 1 receptor ErbB4 [9], or the ErbB4 hetero-dimerizing partner ErB2 [10] resulted in aborted trabecular growth which was accompanied by embryonic lethality, suggesting that neuregulin 1 signaling might regulate cardiomyocyte proliferation during early cardiac development

  • We further examined the impact of NRG1b1 treatment on cardiomyocyte renewal by monitoring DNA synthesis using either bromodeoxyuridine (BrdU, delivered via implanted osmotic mini-pumps) or tritiated thymidine (3H-Thy, delivered via IP injection) incorporation

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Summary

Introduction

Many forms of cardiovascular disease are associated with acute or chronic cardiomyocyte loss. Ablation of the Neuregulin 1 gene [7, 8], the neuregulin 1 receptor ErbB4 [9], or the ErbB4 hetero-dimerizing partner ErB2 [10] resulted in aborted trabecular growth which was accompanied by embryonic lethality, suggesting that neuregulin 1 signaling might regulate cardiomyocyte proliferation during early cardiac development. This view was supported by several cell culture studies [11, 12], subsequent gene targeting experiments suggested that neuregulin 1 regulates cardiomyocyte differentiation and maturation during early development [13, 14]

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