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

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.

• Authors: Konstantinos E Hatzistergos, Ellena C Paulino, Raul A Dulce, Lauro M Takeuchi, Michael A Bellio, Shathiyah Kulandavelu, Yenong Cao, Wayne Balkan, Rosemeire M Kanashiro-Takeuchi, Joshua M Hare
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 4 Issue 7 (Jul 15 2015) ISSN: 2047-9980 [Electronic] England
• PMID: 26178404 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Chemical References

• Biomarkers
• Adh5 protein, mouse
• Alcohol Dehydrogenase
• Proto-Oncogene Proteins c-kit
• Leukocyte Common Antigens
• Ptprc protein, mouse

Topics

• Adult Stem Cells (enzymology, pathology)
• Alcohol Dehydrogenase (deficiency, genetics)
• Animals
• Biomarkers (metabolism)
• Calcium Signaling
• Cell Proliferation
• Cells, Cultured
• Disease Models, Animal
• Homozygote
• Leukocyte Common Antigens (deficiency)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Contraction
• Myocardial Infarction (enzymology, genetics, pathology, physiopathology)
• Myocytes, Cardiac (enzymology, pathology)
• Neovascularization, Physiologic
• Phenotype
• Proto-Oncogene Proteins c-kit (metabolism)
• Regeneration
• Stroke Volume
• Time Factors