Activin a and follistatin-like 3 determine the susceptibility of heart to ischemic injury

Yuichi Oshima, Noriyuki Ouchi, Masayuki Shimano, David R. Pimentel, Kyriakos N. Papanicolaou, Kalyani D. Panse, Kunihiro Tsuchida, Enrique Lara-Pezzi, Se Jin Lee, Kenneth Walsh

Research output: Contribution to journalArticle

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Abstract

BACKGROUND-: Transforming growth factor-β family cytokines have diverse actions in the maintenance of cardiac homeostasis. Activin A is a member of this family whose regulation and function in heart are not well understood at a molecular level. Follistatin-like 3 (Fstl3) is an extracellular regulator of activin A protein, and its function in the heart is also unknown. METHODS AND RESULTS-: We analyzed the expression of various transforming growth factor-β superfamily cytokines and their binding partners in mouse heart. Activin βA and Fstl3 were upregulated in models of myocardial injury. Overexpression of activin A with an adenoviral vector (Ad-actβA) or treatment with recombinant activin A protein protected cultured myocytes from hypoxia/reoxygenation-induced apoptosis. Systemic overexpression of activin A in mice by intravenous injection of Ad-actβA protected hearts from ischemia/reperfusion injury. Activin A induced the expression of Bcl-2, and ablation of Bcl-2 by small interfering RNA abrogated its protective action in myocytes. The protective effect of activin A on cultured myocytes was abolished by treatment with Fstl3 or by a pharmacological activin receptor-like kinase inhibitor. Cardiac-specific Fstl3 knockout mice showed significantly smaller infarcts after ischemia/reperfusion injury that was accompanied by reduced apoptosis. CONCLUSIONS-: Activin A and Fstl3 are induced in heart by myocardial stress. Activin A protects myocytes from death, and this activity is antagonized by Fstl3. Thus, the relative expression levels of these factors after injury is a determinant of cell survival in the heart.

Original languageEnglish
Pages (from-to)1606-1615
Number of pages10
JournalCirculation
Volume120
Issue number16
DOIs
Publication statusPublished - 01-10-2009

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Follistatin
Activins
Wounds and Injuries
Muscle Cells
Transforming Growth Factors
Reperfusion Injury
Activin Receptors
activin A
Apoptosis
Cytokines
Knockout Mice
Intravenous Injections
Small Interfering RNA
Cell Survival
Proteins
Homeostasis
Maintenance
Pharmacology

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Oshima, Y., Ouchi, N., Shimano, M., Pimentel, D. R., Papanicolaou, K. N., Panse, K. D., ... Walsh, K. (2009). Activin a and follistatin-like 3 determine the susceptibility of heart to ischemic injury. Circulation, 120(16), 1606-1615. https://doi.org/10.1161/CIRCULATIONAHA.109.872200
Oshima, Yuichi ; Ouchi, Noriyuki ; Shimano, Masayuki ; Pimentel, David R. ; Papanicolaou, Kyriakos N. ; Panse, Kalyani D. ; Tsuchida, Kunihiro ; Lara-Pezzi, Enrique ; Lee, Se Jin ; Walsh, Kenneth. / Activin a and follistatin-like 3 determine the susceptibility of heart to ischemic injury. In: Circulation. 2009 ; Vol. 120, No. 16. pp. 1606-1615.
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Oshima, Y, Ouchi, N, Shimano, M, Pimentel, DR, Papanicolaou, KN, Panse, KD, Tsuchida, K, Lara-Pezzi, E, Lee, SJ & Walsh, K 2009, 'Activin a and follistatin-like 3 determine the susceptibility of heart to ischemic injury', Circulation, vol. 120, no. 16, pp. 1606-1615. https://doi.org/10.1161/CIRCULATIONAHA.109.872200

Activin a and follistatin-like 3 determine the susceptibility of heart to ischemic injury. / Oshima, Yuichi; Ouchi, Noriyuki; Shimano, Masayuki; Pimentel, David R.; Papanicolaou, Kyriakos N.; Panse, Kalyani D.; Tsuchida, Kunihiro; Lara-Pezzi, Enrique; Lee, Se Jin; Walsh, Kenneth.

In: Circulation, Vol. 120, No. 16, 01.10.2009, p. 1606-1615.

Research output: Contribution to journalArticle

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T1 - Activin a and follistatin-like 3 determine the susceptibility of heart to ischemic injury

AU - Oshima, Yuichi

AU - Ouchi, Noriyuki

AU - Shimano, Masayuki

AU - Pimentel, David R.

AU - Papanicolaou, Kyriakos N.

AU - Panse, Kalyani D.

AU - Tsuchida, Kunihiro

AU - Lara-Pezzi, Enrique

AU - Lee, Se Jin

AU - Walsh, Kenneth

PY - 2009/10/1

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N2 - BACKGROUND-: Transforming growth factor-β family cytokines have diverse actions in the maintenance of cardiac homeostasis. Activin A is a member of this family whose regulation and function in heart are not well understood at a molecular level. Follistatin-like 3 (Fstl3) is an extracellular regulator of activin A protein, and its function in the heart is also unknown. METHODS AND RESULTS-: We analyzed the expression of various transforming growth factor-β superfamily cytokines and their binding partners in mouse heart. Activin βA and Fstl3 were upregulated in models of myocardial injury. Overexpression of activin A with an adenoviral vector (Ad-actβA) or treatment with recombinant activin A protein protected cultured myocytes from hypoxia/reoxygenation-induced apoptosis. Systemic overexpression of activin A in mice by intravenous injection of Ad-actβA protected hearts from ischemia/reperfusion injury. Activin A induced the expression of Bcl-2, and ablation of Bcl-2 by small interfering RNA abrogated its protective action in myocytes. The protective effect of activin A on cultured myocytes was abolished by treatment with Fstl3 or by a pharmacological activin receptor-like kinase inhibitor. Cardiac-specific Fstl3 knockout mice showed significantly smaller infarcts after ischemia/reperfusion injury that was accompanied by reduced apoptosis. CONCLUSIONS-: Activin A and Fstl3 are induced in heart by myocardial stress. Activin A protects myocytes from death, and this activity is antagonized by Fstl3. Thus, the relative expression levels of these factors after injury is a determinant of cell survival in the heart.

AB - BACKGROUND-: Transforming growth factor-β family cytokines have diverse actions in the maintenance of cardiac homeostasis. Activin A is a member of this family whose regulation and function in heart are not well understood at a molecular level. Follistatin-like 3 (Fstl3) is an extracellular regulator of activin A protein, and its function in the heart is also unknown. METHODS AND RESULTS-: We analyzed the expression of various transforming growth factor-β superfamily cytokines and their binding partners in mouse heart. Activin βA and Fstl3 were upregulated in models of myocardial injury. Overexpression of activin A with an adenoviral vector (Ad-actβA) or treatment with recombinant activin A protein protected cultured myocytes from hypoxia/reoxygenation-induced apoptosis. Systemic overexpression of activin A in mice by intravenous injection of Ad-actβA protected hearts from ischemia/reperfusion injury. Activin A induced the expression of Bcl-2, and ablation of Bcl-2 by small interfering RNA abrogated its protective action in myocytes. The protective effect of activin A on cultured myocytes was abolished by treatment with Fstl3 or by a pharmacological activin receptor-like kinase inhibitor. Cardiac-specific Fstl3 knockout mice showed significantly smaller infarcts after ischemia/reperfusion injury that was accompanied by reduced apoptosis. CONCLUSIONS-: Activin A and Fstl3 are induced in heart by myocardial stress. Activin A protects myocytes from death, and this activity is antagonized by Fstl3. Thus, the relative expression levels of these factors after injury is a determinant of cell survival in the heart.

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Oshima Y, Ouchi N, Shimano M, Pimentel DR, Papanicolaou KN, Panse KD et al. Activin a and follistatin-like 3 determine the susceptibility of heart to ischemic injury. Circulation. 2009 Oct 1;120(16):1606-1615. https://doi.org/10.1161/CIRCULATIONAHA.109.872200