title: 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.
  
  
  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.affiliation: Interdisciplinary Stem Cell Institute, University of Miami, FL (K.E.H., E.C.P., R.A.D., L.M.T., M.A.B., S.K., Y.C., W.B., R.M.K.T., J.M.H.).
authors.forename: Konstantinos E
authors.initials: KE
authors.lastname: Hatzistergos
authors.affiliation: Interdisciplinary Stem Cell Institute, University of Miami, FL (K.E.H., E.C.P., R.A.D., L.M.T., M.A.B., S.K., Y.C., W.B., R.M.K.T., J.M.H.).
authors.forename: Ellena C
authors.initials: EC
authors.lastname: Paulino
authors.affiliation: Interdisciplinary Stem Cell Institute, University of Miami, FL (K.E.H., E.C.P., R.A.D., L.M.T., M.A.B., S.K., Y.C., W.B., R.M.K.T., J.M.H.).
authors.forename: Raul A
authors.initials: RA
authors.lastname: Dulce
authors.affiliation: Interdisciplinary Stem Cell Institute, University of Miami, FL (K.E.H., E.C.P., R.A.D., L.M.T., M.A.B., S.K., Y.C., W.B., R.M.K.T., J.M.H.).
authors.forename: Lauro M
authors.initials: LM
authors.lastname: Takeuchi
authors.affiliation: Interdisciplinary Stem Cell Institute, University of Miami, FL (K.E.H., E.C.P., R.A.D., L.M.T., M.A.B., S.K., Y.C., W.B., R.M.K.T., J.M.H.) Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL (M.A.B., R.M.K.T., J.M.H.).
authors.forename: Michael A
authors.initials: MA
authors.lastname: Bellio
authors.affiliation: Interdisciplinary Stem Cell Institute, University of Miami, FL (K.E.H., E.C.P., R.A.D., L.M.T., M.A.B., S.K., Y.C., W.B., R.M.K.T., J.M.H.).
authors.forename: Shathiyah
authors.initials: S
authors.lastname: Kulandavelu
authors.affiliation: Interdisciplinary Stem Cell Institute, University of Miami, FL (K.E.H., E.C.P., R.A.D., L.M.T., M.A.B., S.K., Y.C., W.B., R.M.K.T., J.M.H.).
authors.forename: Yenong
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Interdisciplinary Stem Cell Institute, University of Miami, FL (K.E.H., E.C.P., R.A.D., L.M.T., M.A.B., S.K., Y.C., W.B., R.M.K.T., J.M.H.) Department of Medicine, University of Miami Miller School of Medicine, Miami, FL (W.B., J.M.H.).
authors.forename: Wayne
authors.initials: W
authors.lastname: Balkan
authors.affiliation: Interdisciplinary Stem Cell Institute, University of Miami, FL (K.E.H., E.C.P., R.A.D., L.M.T., M.A.B., S.K., Y.C., W.B., R.M.K.T., J.M.H.) Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL (M.A.B., R.M.K.T., J.M.H.).
authors.forename: Rosemeire M
authors.initials: RM
authors.lastname: Kanashiro-Takeuchi
authors.affiliation: Interdisciplinary Stem Cell Institute, University of Miami, FL (K.E.H., E.C.P., R.A.D., L.M.T., M.A.B., S.K., Y.C., W.B., R.M.K.T., J.M.H.) Department of Medicine, University of Miami Miller School of Medicine, Miami, FL (W.B., J.M.H.) Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL (M.A.B., R.M.K.T., J.M.H.).
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D053687:Adult Stem Cells / Q000201:enzymology* / Q000473:pathology; D000426:Alcohol Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D020013:Calcium Signaling; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006720:Homozygote; D017493:Leukocyte Common Antigens / Q000172:deficiency; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D018919:Neovascularization, Physiologic; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012038:Regeneration; D013318:Stroke Volume; D013997:Time Factors
chemical_list: D015415:Biomarkers; C483598:Adh5 protein, mouse; D000426:Alcohol Dehydrogenase; D019009:Proto-Oncogene Proteins c-kit; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse
keywords: S‐nitrosoglutathione reductase; cardiovascular progenitor/stem cells; heart disease; heart regeneration; nitric oxide signaling