Hypoxia Induces Myocardial Regeneration in Zebrafish

Abstract

Background-Hypoxia plays an important role in many biological/pathological processes. In particular, hypoxia is associated with cardiac ischemia. which, although initially inducing a protective response, will ultimately lead to the death of cardiomyocytes and loss of tissue, severely affecting cardiac functionality. Although myocardial damage/loss remains an insurmountable problem for adult mammals, the same is not true for adult zebrafish, which are able to completely regenerate their heart after extensive injury. Myocardial regeneration in zebrafish involves the dedifferentiation and proliferation of cardiomyocytes to replace the damaged/missing tissue; at present, however, little is known about what factors regulate this process. Methods and Results-We surmised that ventricular amputation would lead to hypoxia induction in the myocardium of zebrafish and that this may play a role in regulating the regeneration of the missing cardiac tissue. Using a combination of O 2 perturbation, conditional transgenics, in vitro cell culture, and microarray analysis, we found that hypoxia induces cardiomyocytes to dedifferentiate and proliferate during heart regeneration in zebrafish and have identified a number of genes that could play a role in this process. Conclusion-These results indicate that hypoxia plays a positive role during heart regeneration, which should be taken into account in future strategies aimed at inducing heart regeneration in humans. (Circulation. 2012;126:3017-3027.)

Building and re-building the heart by cardiomyocyte proliferation

“…In that vein, a recent report by Guimarães-Camboa et al, which examined the regulation of cell stress pathways by Hif1α to promote fetal cardiomyocyte proliferation, provides further contextual support for the role of neonatal oxygen exposure with respect to the exit of cardiomyocytes from the cell cycle (Guimarães-Camboa et al, 2015). Also consistent with this idea is the observation that ventricular resection injury in zebrafish was reported to induce a hypoxia response, with Hif1α implicated as a crucial mediator (Jopling et al, 2012). The manipulation of Yap activity after birth can prevent or extend the capacity for compensatory cardiomyocyte proliferation after injury.…”

Zebrafish as a Model for Studying Cardiac Regeneration

“…Recent studies have also uncovered other factors that influence zebrafish heart regeneration. In brief, hypoxia and inflammatory responses appear to positively regulate CM cell cycle re-entry, whereas hyperoxia, p38a MAPK and miR-133 have negative roles [43][44][45][46].…”

Tumor angiogenesis is caused by single melanoma cells in a reactive oxygen species and NF-κB dependent manner

“…S1A). In addition, hypoxia was determined by hypoxyprobe treatment and subsequent antibody detection, as described previously (Jopling et al, 2012). Again, excised tailfins which were kept under hypoxic conditions showed strong staining, which was not detected in fins from mitf::xmrk fishes (supplementary material Fig.…”