Complement receptor C5aR1 plays an evolutionarily conserved role in successful cardiac regeneration

N Natarajan, Y Abbas, DM Bryant, JM Gonzalez-Rosa… - Circulation, 2018 - Am Heart Assoc
Circulation, 2018Am Heart Assoc
Background: Defining conserved molecular pathways in animal models of successful
cardiac regeneration could yield insight into why adult mammals have inadequate cardiac
regeneration after injury. Insight into the transcriptomic landscape of early cardiac
regeneration from model organisms will shed light on evolutionarily conserved pathways in
successful cardiac regeneration. Methods: Here we describe a cross-species transcriptomic
screen in 3 model organisms for cardiac regeneration: axolotl, neonatal mice, and zebrafish …
Background
Defining conserved molecular pathways in animal models of successful cardiac regeneration could yield insight into why adult mammals have inadequate cardiac regeneration after injury. Insight into the transcriptomic landscape of early cardiac regeneration from model organisms will shed light on evolutionarily conserved pathways in successful cardiac regeneration.
Methods
Here we describe a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration: axolotl, neonatal mice, and zebrafish. Apical resection to remove ≈10% to 20% of ventricular mass was carried out in these model organisms. RNA-sequencing analysis was performed on the hearts harvested at 3 time points: 12, 24, and 48 hours after resection. Sham surgery was used as internal control.
Results
Genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors (activated by complement components, part of the innate immune system) were found to be highly upregulated in all 3 species. This approach revealed induction of gene expression for complement 5a receptor 1 in the regenerating hearts of zebrafish, axolotls, and mice. Inhibition of complement 5a receptor 1 significantly attenuated the cardiomyocyte proliferative response to heart injury in all 3 species. Furthermore, after left ventricular apical resection, the cardiomyocyte proliferative response was diminished in mice with genetic deletion of complement 5a receptor 1.
Conclusions
These data reveal that activation of complement 5a receptor 1 mediates an evolutionarily conserved response that promotes cardiomyocyte proliferation after cardiac injury and identify complement pathway activation as a common pathway of successful heart regeneration.
Am Heart Assoc