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

Konstantinos E. Hatzistergos, Ellena C. Paulino, Raul A. Dulce, Lauro M. Takeuchi, Michael A. Bellio, Shathiyah Kulandavelu, Yenong Cao, Wayne E Balkan, Rosemeire Takeuchi, Joshua Hare

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Abstract

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.

Original languageEnglish (US)
JournalJournal of the American Heart Association
Volume4
Issue number7
DOIs
StatePublished - Jul 15 2015

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Keywords

  • cardiovascular progenitor/stem cells
  • heart disease
  • heart regeneration
  • nitric oxide signaling
  • S‐nitrosoglutathione reductase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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