S-Nitrosoglutathione Reductase Deficiency Enhances the Proliferative Expansion of Adult Heart Progenitors and Myocytes Post Myocardial Infarction

Background: mammalian heart regenerative activity is lost before adulthood but increases after cardiac injury. cardiac repair mechanisms,which involve both endogenous cardiac stem cells (cscs) and cardiomyocyte cell-cycle reentry,are inadequate to achieve full recovery after myocardial infarction (mi). mice deficient in s-nitrosoglutathione reductase (gsnor(-⁄-)),an enzyme regulating s-nitrosothiol turnover,have preserved cardiac function after mi. here,we tested the hypothesis that gsnor activity modulates cardiac cell proliferation in the post-mi adult heart.methods and results: gsnor(-⁄-) and c57bl6/j (wild-type [wt]) mice were subjected to sham operation (n=3 gsnor(-⁄-); n=3 wt) or mi (n=41 gsnor(-⁄-); n=65 wt). compared with wt,gsnor(-⁄-) mice exhibited improved survival,cardiac performance,and architecture after mi,as demonstrated by higher ejection fraction (p<0.05),lower endocardial volumes (p<0.001),and diminished scar size (p<0.05). in addition,cardiomyocytes from post-mi gsnor(-⁄-) hearts exhibited faster calcium decay and sarcomeric relaxation times (p<0.001). immunophenotypic analysis illustrated that post-mi gsnor(-⁄-) hearts demonstrated enhanced neovascularization (p<0.001),c-kit(+) csc abundance (p=0.013),and a ≈3-fold increase in proliferation of adult cardiomyocytes and c-kit(+)/cd45(-) cscs (p<0.0001 and p=0.023,respectively) as measured by using 5-bromodeoxyuridine.conclusions: loss of gsnor confers enhanced post-mi cardiac regenerative activity,characterized by enhanced turnover of cardiomyocytes and cscs. endogenous denitrosylases exert an inhibitory effect over cardiac repair mechanisms and therefore represents a potential novel therapeutic target. © 2015 the authors. published on behalf of the american heart association,inc.,by wiley blackwell.