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 language | English (US) |
|---|---|
| Journal | Journal of the American Heart Association |
| Volume | 4 |
| Issue number | 7 |
| DOIs | |
| State | Published - 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
Cite this
S-Nitrosoglutathione Reductase Deficiency Enhances the Proliferative Expansion of Adult Heart Progenitors and Myocytes Post Myocardial Infarction. / Hatzistergos, Konstantinos E.; Paulino, Ellena C.; Dulce, Raul A.; Takeuchi, Lauro M.; Bellio, Michael A.; Kulandavelu, Shathiyah; Cao, Yenong; Balkan, Wayne E; Takeuchi, Rosemeire; Hare, Joshua.
In: Journal of the American Heart Association, Vol. 4, No. 7, 15.07.2015.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - S-Nitrosoglutathione Reductase Deficiency Enhances the Proliferative Expansion of Adult Heart Progenitors and Myocytes Post Myocardial Infarction
AU - Hatzistergos, Konstantinos E.
AU - Paulino, Ellena C.
AU - Dulce, Raul A.
AU - Takeuchi, Lauro M.
AU - Bellio, Michael A.
AU - Kulandavelu, Shathiyah
AU - Cao, Yenong
AU - Balkan, Wayne E
AU - Takeuchi, Rosemeire
AU - Hare, Joshua
PY - 2015/7/15
Y1 - 2015/7/15
N2 - 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.
AB - 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.
KW - cardiovascular progenitor/stem cells
KW - heart disease
KW - heart regeneration
KW - nitric oxide signaling
KW - S‐nitrosoglutathione reductase
UR - http://www.scopus.com/inward/record.url?scp=85018231883&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018231883&partnerID=8YFLogxK
U2 - 10.1161/JAHA.115.001974
DO - 10.1161/JAHA.115.001974
M3 - Article
C2 - 26178404
AN - SCOPUS:85018231883
VL - 4
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
SN - 2047-9980
IS - 7
ER -