p38α MAPK regulates myocardial regeneration in zebrafish

Abstract

Although adult mammals are unable to significantly regenerate their heart, this is not the case for a number of other vertebrate species. In particular, zebrafish are able to fully regenerate their heart following amputation of up to 20% of the ventricle. Soon after amputation, cardiomyocytes dedifferentiate and proliferate to regenerate the missing tissue. More recently, identical results have also been obtained in neonatal mice. Ventricular amputation of neonates leads to a robust regenerative response driven by the proliferation of existing cardiomyocytes in a similar manner to zebrafish. However, this ability is progressively lost during the first week of birth. The fact that adult zebrafish retain the capacity to regenerate their heart suggests that they either possess a unique regenerative mechanism, or that adult mammals lose/ inhibit this process. p38α ΜAPK has previously been shown to negatively regulate the proliferation of adult mammalian cardiomyocytes. We sought to determine whether a similar mechanism exists in adult zebrafish, and whether this needs to be overcome to allow regeneration to proceed. To determine whether p38α ΜAPK also regulates zebrafish cardiomyocytes in a similar manner, we generated conditional transgenic zebrafish in which either dominant-negative or active p38α ΜAPK are specifically expressed in cardiomyocytes. We found that active p38α ΜAPK but not dominantnegative p38α ΜAPK blocks proliferation of adult zebrafish cardiomyocytes and, consequently, heart regeneration as well. It appears that adult zebrafish cardiomyocytes share many characteristics with adult mammalian cardiomyocytes, including p38α MAPK-mediated cell cycle inhibition. These findings raise the possibility that zebrafish-like heart regeneration could be achieved in adult mammals.

Hydrogen peroxide primes heart regeneration with a derepression mechanism

“…In contrast to previous reports on a negative role of p38 MAPK in mammalian and zebrafish heart regeneration [44,45], our data support that H 2 O 2 in the epicardium (Figure 1) is essential for elevating phosphorylation of Erk1/2 MAPK through repression of Dusp6 during zebrafish heart regeneration ( Figures 3-5 and 7). Our data are aligned well with the previous reports that H 2 O 2 directly oxidizes Dusp6 in TNFα-induced cell death and ovarian cancers, leading to ubiquitination and subsequent proteasome degradation of Dusp6 and thus aberrant Erk1/2 activation [37,38] (Figure 5).…”

How to make a cardiomyocyte

“…The mitogen-activated protein kinase (MAPK) p38α (Mapk14) signaling pathway is a key target for such studies (Engel et al, 2005(Engel et al, , 2006Jopling et al, 2012). In neonatal mice, the miR-15 family and the transcription factor Meis homeobox 1 (MEIS1) play a role in the postnatal loss of cardiomyocyte proliferation.…”

Mending a Faltering Heart

“…Cardiomyocyte renewal can be promoted by inhibiting negative regulators of proliferation, such as the Hippo signaling pathway 54 and the p38 mitogen-activated protein kinase pathway, 55 or activating the endogenous cardiomyocyte proliferation program through neuregulin 1 signaling, 51 hypoxia and cell cycle regulators polo-like kinase 1 (plk1), and mitotic checkpoint kinase mps1. 30,56 Micro-RNAs (miRNAs) can also coordinately regulate cardiomyogenic programs.…”