Neonatal vulnerability to ischemia and reperfusion: Cardioplegic arrest causes greater myocardial apoptosis in neonatal lambs than in mature lambs

Mohsen Karimi, Li Xing Wang, James M. Hammel, Christopher E. Mascio, Mohamed Abdulhamid, Elesa W. Barner, Thomas D. Scholz, Jeffrey L. Segar, Wei Gen Li, Scott D. Niles, Christopher A. Caldarone, Ralph J. Damiano, Frank W. Sellke, Antonio F. Corno

Research output: Contribution to journalArticle

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Abstract

Objectives: Apoptosis is a mechanism for deletion of injured or obsolete cells that is distinct from necrosis and mediated by mitochondrial release of cytochrome c caspase activation. Because myocardial apoptosis is a part of normal fetal and postnatal maturation, we hypothesize that neonatal myocardium is more vulnerable to undergo myocardial apoptosis than mature myocardium after cardioplegic arrest. Methods: Newborn and mature lambs (n = 5 in each group) underwent cardiopulmonary bypass, antegrade crystalloid hyperkalemic cardioplegic arrest for 60 minutes, and a 6-hour recovery period. Myocardium was examined by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL), Western blotting, in vitro kinase assays, and fluorometric assays of the activity of caspases 3, 8, and 9. Myocardium from nonoperated control subjects (n = 5 in each age group) was also obtained. Results: More TUNEL-positive nuclei were present in the newborn postcardioplegic myocardium (P = .04). Caspase 3, 8, and 9 activities were 1.6-fold, 1.5-fold, and 1.4-fold greater in the newborn postcardioplegic myocardium (P = .04, P = .01, and P = .01, respectively). The Bax/Bcl-2 ratio was higher in the newborn postcardioplegic myocardium (P = .04). Apoptosis signal-regulating kinase 1 activity and cleaved caspase 3 levels were higher in the newborn postcardioplegic myocardium (P = .02 and P = .009). Mitochondrial release of cytochrome c was greater in the newborn postcardioplegic myocardium (P = .009). Conclusions: The increased Bax/Bcl-2 ratio in the newborn myocardium suggests a proapoptotic state that is manifested by greater TUNEL staining, cytochrome c release, and cleavage of caspase 3. Increased apoptosis signal-regulating kinase 1 activity suggests greater oxidative stress, immature mechanisms to ameliorate oxidative stress, or both in the neonatal myocardium. Mitochondrial release of cytochrome c suggests that apoptosis-related mitochondrial dysfunction might contribute to early postoperative myocardial dysfunction in the neonate.

Original languageEnglish (US)
Pages (from-to)490-497
Number of pages8
JournalJournal of Thoracic and Cardiovascular Surgery
Volume127
Issue number2
DOIs
StatePublished - Feb 2004

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Reperfusion
Myocardium
Ischemia
Apoptosis
Newborn Infant
Cytochromes c
Caspase 3
In Situ Nick-End Labeling
MAP Kinase Kinase Kinase 5
Caspase 9
Caspase 8
Oxidative Stress
Digoxigenin
DNA Nucleotidylexotransferase
Caspases
Cardiopulmonary Bypass
Necrosis
Phosphotransferases
Age Groups
Western Blotting

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Neonatal vulnerability to ischemia and reperfusion : Cardioplegic arrest causes greater myocardial apoptosis in neonatal lambs than in mature lambs. / Karimi, Mohsen; Wang, Li Xing; Hammel, James M.; Mascio, Christopher E.; Abdulhamid, Mohamed; Barner, Elesa W.; Scholz, Thomas D.; Segar, Jeffrey L.; Li, Wei Gen; Niles, Scott D.; Caldarone, Christopher A.; Damiano, Ralph J.; Sellke, Frank W.; Corno, Antonio F.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 127, No. 2, 02.2004, p. 490-497.

Research output: Contribution to journalArticle

Karimi, M, Wang, LX, Hammel, JM, Mascio, CE, Abdulhamid, M, Barner, EW, Scholz, TD, Segar, JL, Li, WG, Niles, SD, Caldarone, CA, Damiano, RJ, Sellke, FW & Corno, AF 2004, 'Neonatal vulnerability to ischemia and reperfusion: Cardioplegic arrest causes greater myocardial apoptosis in neonatal lambs than in mature lambs', Journal of Thoracic and Cardiovascular Surgery, vol. 127, no. 2, pp. 490-497. https://doi.org/10.1016/j.jtcvs.2003.07.052
Karimi, Mohsen ; Wang, Li Xing ; Hammel, James M. ; Mascio, Christopher E. ; Abdulhamid, Mohamed ; Barner, Elesa W. ; Scholz, Thomas D. ; Segar, Jeffrey L. ; Li, Wei Gen ; Niles, Scott D. ; Caldarone, Christopher A. ; Damiano, Ralph J. ; Sellke, Frank W. ; Corno, Antonio F. / Neonatal vulnerability to ischemia and reperfusion : Cardioplegic arrest causes greater myocardial apoptosis in neonatal lambs than in mature lambs. In: Journal of Thoracic and Cardiovascular Surgery. 2004 ; Vol. 127, No. 2. pp. 490-497.
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abstract = "Objectives: Apoptosis is a mechanism for deletion of injured or obsolete cells that is distinct from necrosis and mediated by mitochondrial release of cytochrome c caspase activation. Because myocardial apoptosis is a part of normal fetal and postnatal maturation, we hypothesize that neonatal myocardium is more vulnerable to undergo myocardial apoptosis than mature myocardium after cardioplegic arrest. Methods: Newborn and mature lambs (n = 5 in each group) underwent cardiopulmonary bypass, antegrade crystalloid hyperkalemic cardioplegic arrest for 60 minutes, and a 6-hour recovery period. Myocardium was examined by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL), Western blotting, in vitro kinase assays, and fluorometric assays of the activity of caspases 3, 8, and 9. Myocardium from nonoperated control subjects (n = 5 in each age group) was also obtained. Results: More TUNEL-positive nuclei were present in the newborn postcardioplegic myocardium (P = .04). Caspase 3, 8, and 9 activities were 1.6-fold, 1.5-fold, and 1.4-fold greater in the newborn postcardioplegic myocardium (P = .04, P = .01, and P = .01, respectively). The Bax/Bcl-2 ratio was higher in the newborn postcardioplegic myocardium (P = .04). Apoptosis signal-regulating kinase 1 activity and cleaved caspase 3 levels were higher in the newborn postcardioplegic myocardium (P = .02 and P = .009). Mitochondrial release of cytochrome c was greater in the newborn postcardioplegic myocardium (P = .009). Conclusions: The increased Bax/Bcl-2 ratio in the newborn myocardium suggests a proapoptotic state that is manifested by greater TUNEL staining, cytochrome c release, and cleavage of caspase 3. Increased apoptosis signal-regulating kinase 1 activity suggests greater oxidative stress, immature mechanisms to ameliorate oxidative stress, or both in the neonatal myocardium. Mitochondrial release of cytochrome c suggests that apoptosis-related mitochondrial dysfunction might contribute to early postoperative myocardial dysfunction in the neonate.",
author = "Mohsen Karimi and Wang, {Li Xing} and Hammel, {James M.} and Mascio, {Christopher E.} and Mohamed Abdulhamid and Barner, {Elesa W.} and Scholz, {Thomas D.} and Segar, {Jeffrey L.} and Li, {Wei Gen} and Niles, {Scott D.} and Caldarone, {Christopher A.} and Damiano, {Ralph J.} and Sellke, {Frank W.} and Corno, {Antonio F.}",
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T1 - Neonatal vulnerability to ischemia and reperfusion

T2 - Cardioplegic arrest causes greater myocardial apoptosis in neonatal lambs than in mature lambs

AU - Karimi, Mohsen

AU - Wang, Li Xing

AU - Hammel, James M.

AU - Mascio, Christopher E.

AU - Abdulhamid, Mohamed

AU - Barner, Elesa W.

AU - Scholz, Thomas D.

AU - Segar, Jeffrey L.

AU - Li, Wei Gen

AU - Niles, Scott D.

AU - Caldarone, Christopher A.

AU - Damiano, Ralph J.

AU - Sellke, Frank W.

AU - Corno, Antonio F.

PY - 2004/2

Y1 - 2004/2

N2 - Objectives: Apoptosis is a mechanism for deletion of injured or obsolete cells that is distinct from necrosis and mediated by mitochondrial release of cytochrome c caspase activation. Because myocardial apoptosis is a part of normal fetal and postnatal maturation, we hypothesize that neonatal myocardium is more vulnerable to undergo myocardial apoptosis than mature myocardium after cardioplegic arrest. Methods: Newborn and mature lambs (n = 5 in each group) underwent cardiopulmonary bypass, antegrade crystalloid hyperkalemic cardioplegic arrest for 60 minutes, and a 6-hour recovery period. Myocardium was examined by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL), Western blotting, in vitro kinase assays, and fluorometric assays of the activity of caspases 3, 8, and 9. Myocardium from nonoperated control subjects (n = 5 in each age group) was also obtained. Results: More TUNEL-positive nuclei were present in the newborn postcardioplegic myocardium (P = .04). Caspase 3, 8, and 9 activities were 1.6-fold, 1.5-fold, and 1.4-fold greater in the newborn postcardioplegic myocardium (P = .04, P = .01, and P = .01, respectively). The Bax/Bcl-2 ratio was higher in the newborn postcardioplegic myocardium (P = .04). Apoptosis signal-regulating kinase 1 activity and cleaved caspase 3 levels were higher in the newborn postcardioplegic myocardium (P = .02 and P = .009). Mitochondrial release of cytochrome c was greater in the newborn postcardioplegic myocardium (P = .009). Conclusions: The increased Bax/Bcl-2 ratio in the newborn myocardium suggests a proapoptotic state that is manifested by greater TUNEL staining, cytochrome c release, and cleavage of caspase 3. Increased apoptosis signal-regulating kinase 1 activity suggests greater oxidative stress, immature mechanisms to ameliorate oxidative stress, or both in the neonatal myocardium. Mitochondrial release of cytochrome c suggests that apoptosis-related mitochondrial dysfunction might contribute to early postoperative myocardial dysfunction in the neonate.

AB - Objectives: Apoptosis is a mechanism for deletion of injured or obsolete cells that is distinct from necrosis and mediated by mitochondrial release of cytochrome c caspase activation. Because myocardial apoptosis is a part of normal fetal and postnatal maturation, we hypothesize that neonatal myocardium is more vulnerable to undergo myocardial apoptosis than mature myocardium after cardioplegic arrest. Methods: Newborn and mature lambs (n = 5 in each group) underwent cardiopulmonary bypass, antegrade crystalloid hyperkalemic cardioplegic arrest for 60 minutes, and a 6-hour recovery period. Myocardium was examined by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL), Western blotting, in vitro kinase assays, and fluorometric assays of the activity of caspases 3, 8, and 9. Myocardium from nonoperated control subjects (n = 5 in each age group) was also obtained. Results: More TUNEL-positive nuclei were present in the newborn postcardioplegic myocardium (P = .04). Caspase 3, 8, and 9 activities were 1.6-fold, 1.5-fold, and 1.4-fold greater in the newborn postcardioplegic myocardium (P = .04, P = .01, and P = .01, respectively). The Bax/Bcl-2 ratio was higher in the newborn postcardioplegic myocardium (P = .04). Apoptosis signal-regulating kinase 1 activity and cleaved caspase 3 levels were higher in the newborn postcardioplegic myocardium (P = .02 and P = .009). Mitochondrial release of cytochrome c was greater in the newborn postcardioplegic myocardium (P = .009). Conclusions: The increased Bax/Bcl-2 ratio in the newborn myocardium suggests a proapoptotic state that is manifested by greater TUNEL staining, cytochrome c release, and cleavage of caspase 3. Increased apoptosis signal-regulating kinase 1 activity suggests greater oxidative stress, immature mechanisms to ameliorate oxidative stress, or both in the neonatal myocardium. Mitochondrial release of cytochrome c suggests that apoptosis-related mitochondrial dysfunction might contribute to early postoperative myocardial dysfunction in the neonate.

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