Reactive oxygen species during heart regeneration in zebrafish: Lessons for future clinical therapies

Abstract

In humans, myocardial infarction (MI) is associated with irreversible damage to heart tissue, resulting in increased morbidity and mortality in patients. By comparison, the zebrafish (Danio rerio) is capable of repairing damaged and injured hearts by activating a full regenerative response. By studying model organisms that can regenerate loss heart tissue following injury, such as the zebrafish, a greater insight will be gained into the molecular pathways that can induce and sustain a regenerative response following injury. There is hope that such information may lead to new treatments or therapies aimed at stimulating a better regenerative response in humans that have suffered heart attacks. Recent findings in zebrafish have highlighted an important role for sustained elevated levels of Reactive Oxygen Species (ROS), including hydrogen peroxide (H2O2) in the promotion of a regenerative response. Given that elevated levels of H2O2 can be harmful, simply elevating ROS levels directly may not be easy or practical to translate clinically. An alternative approach would be to identify the critical downstream targets of ROS in the promotion of heart regeneration, and then target these clinically using drugs. One such family of potential downstream targets of ROS during heart regeneration are the family of protein tyrosine phosphatases (PTPs), which are known to be exquisitely sensitive to redox regulation and whose inhibition have been linked to the promotion of heart regeneration in zebrafish. In this review, we present an overview of the zebrafish as a model organism for studying cardiac regeneration, including the molecular mechanisms by which cardiac regeneration occurs in response to injury. We then present recent findings linking elevated ROS levels to heart regeneration and their potential downstream targets, the PTPs, including protein tyrosine phosphatase 1B (PTP1B) and the dual specificity phosphatase 6 (DUSP6) in the promotion of heart regeneration.

Reactive Oxygen Species Signaling Differentially Controls Wound Healing and Regeneration

“…Collectively, our findings provide insights into cytoskeletal-mediated mechanisms of early wound healing in planarians, and our investigation of both wound healing and regeneration in the same model system (at the same wound) has enabled us to parse out differences in two processes that were once thought to be inseparable. Our investigations identified ROS, which are well known regulators of both wound healing and regeneration [12][13][14][15][16][17][18][19][20][21] , as differential controllers of wound repair mechanisms. We show that ROS-mediated jun-1 expression is a regulator of epithelial stretching during wound closure, while ROS signaling upstream of hsp70 expression governs the regenerative program.…”

“…Importantly, the production of injury-induced ROS is a conserved wound response in both plants and animals 11 . The data reveal that ROS accumulation peaks during both wound healing and regeneration, and ROS inhibition has been shown to both delay wound closure rates and prevent regeneration in multiple animal models [12][13][14][15][16][17] . ROS are capable of inducing vasoconstriction and the recruitment of leukocytes to the wound site after injury 18,19 .…”

The Emerging Role of Protein Phosphatase in Regeneration

“…During zebrafish heart regeneration, the continuous increase in reactive oxygen species (ROS) can promote the regeneration response. ROS exists in multiple forms and is defined as highly reactive ions and free radicals in the form of hydrogen peroxide (H 2 O 2 ), superoxide anion (O 2− ), and hydroxyl radical (OH − ) [ 92 ]. The recent finding in zebrafish showed that DUSP6 is a potential downstream target of ROS and can effectively regulate cardiac regeneration ( Figure 4 ) [ 92 ].…”

Metabolic Regulation of Cardiac Regeneration

“…Moreover, a research found that ROS altered the activity of metabolically critical enzymes and hence played a role in cardiac regeneration of zebrafish. Since elevated H 2 O 2 levels are detrimental, investigators identify protein tyrosine phosphatase 1b (Ptp1b) as a downstream target of ROS and propose that inhibition of Ptp1b promotes myocardial regeneration (20). In addition, MSI-1436, a small molecule inhibitor, selectively represses Ptp1b and hence promotes regeneration (21).…”