16 - Endothelial nitric oxide synthase plays a protective role against myocardial infarction

https://doi.org/10.1016/j.freeradbiomed.2018.10.018Get rights and content

Redox signaling has been implicated in the loss of proliferative/regenerative ability of cardiomyocytes (CMs) after birth. This is one of the main reasons why a mature, aged heart cannot regenerate following an extensive inschemic event, such as myocardial infarction (MI). Based on our previous studies on the roles played by endothelial nitric oxide synthase (eNOS) on endothelial cell (EC) and CM proliferation, we hypothesized that eNOS signaling could play a protective role against MI. For this, we used an MI mouse model (permanent LAD ligation). These mice were injected in the muscle wall with different combinations of ECs and CMs isolated from either WT or KO eNOS neonatal mice. Cells were first co-cultured in hanging drops for ~5 days until formation of 3D vascularized cardiac spheroids (VCSs) and then transplanted in adult MI mice. Infarcted animals received either vehicle (media) or a suspension of VCSs in media. Adult mice received VCSs generated by co-culturing either: i) WT CMs and WT ECs; or ii) WT CMs and KO ECs; or iii) KO CMs and WT ECs. Our analysis 28 days following the procedure showed that the higher ejection fraction measured in VCS-injected mice compared with animals receiving media-only (61% ± 4% and 41% ± 11%, respectively) was dependent on eNOS presence in both ECs and CMs. Specifically, genetic deletion of eNOS in either KO ECs or KO CMs in group (ii) and (iii) reduced the ejection fraction to 40% ± 5% and 46% ± 2%, respectively. Therefore, our results strongly suggest that eNOS may play a major role via both an autocrine and paracrine mechanism. Current studies are focusing on evaluating the mechanism(s) for this eNOS-mediated protective role, possibly by promoting angiogenesis and/or proliferation, together with inhibition of inflammatory pathways. A better understanding of the eNOS-mediated protective role may have significant therapeutical impact in heart failure patients.

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