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Minocycline inhibits caspase activation and reactivation, increases the ratio of XIAP to smac/DIABLO, and reduces the mitochondrial leakage of cytochrome C and smac/DIABLO

Minocycline inhibits caspase activation and reactivation, increases the ratio of XIAP to smac/DIABLO, and reduces the mitochondrial leakage of cytochrome C and smac/DIABLO
Minocycline inhibits caspase activation and reactivation, increases the ratio of XIAP to smac/DIABLO, and reduces the mitochondrial leakage of cytochrome C and smac/DIABLO
Objectives: This study is aimed at investigating the novel use of minocycline for cardiac protection during ischemia/reperfusion (I/R) injury, as well as its mechanism of action.
Background: Minocycline is a tetracycline with anti-inflammatory properties, which is used clinically for the treatment of diseases such as urethritis and rheumatoid arthritis. Experimentally, minocycline has also been shown to be neuroprotective in animal models of cerebral ischemia and to delay progression and improve survival in mouse models of neurodegenerative diseases.
Methods: We studied 62 rat intact hearts exposed to I/R and cell cultures of neonatal and adult rat ventricular myocytes.
Results: Minocycline significantly reduced necrotic and apoptotic cell death, both in neonatal and adult myocytes, not only when given prior to hypoxia (p < 0.001), but also at reoxygenation (p < 0.05). Moreover, in the intact heart exposed to I/R, in vivo treatment with minocycline promoted hemodynamic recovery (p < 0.001) and cell survival, with reduction of infarct size (p < 0.001), cardiac release of creatine phosphokinase (p < 0.001), and apoptotic cell death (p < 0.001). In regard to its antiapoptotic mechanism of action, minocycline significantly reduced the expression level of initiator caspases, increased the ratio of XIAP to Smac/DIABLO at both the messenger RNA and protein level, and prevented mitochondrial release of cytochrome c and Smac/DIABLO (all, p < 0.05). These synergistic actions dramatically prevent the post-ischemic induction of caspase activity associated with cardiac I/R injury.
Conclusions: Because of its safety record and multiple novel mechanisms of action, minocycline may be a valuable cardioprotective agent to ameliorate cardiac dysfunction and cell loss associated with I/R injury.
reperfusion injury, survival, enzymology, animals, rats, heart, proteins, injuries, adult, myocardial infarction, cardiac, rheumatoid arthritis, cell survival, activity, sprague-dawley
0735-1097
865-874
Scarabelli, Tiziano M.
ac96a777-880e-4e39-9884-f11a0978da35
Stephanou, Anastasis
e9d502e8-693c-4458-a3c6-5e2844665db3
Pasini, Evasio
42f0e7e2-ef74-4f6f-bee7-ca2f8ce506d2
Gitti, Gianluca
5f875800-dad6-4405-aa76-2f3197788116
Townsend, Paul
54e7bb11-feba-4886-b792-ab0f93c9c734
Lawrence, Kevin
fe8c9942-70e6-48f7-bfe5-94b81105ec28
Chen-Scarabelli, Carol
bf53cd01-66c4-4d7e-859c-9da789e8ba49
Saravolatz, Louis
e7a9e7ec-3371-4087-9ed2-db267f3c1d44
Latchman, David
bb096dcc-99be-44a2-85f2-34b776de6abc
Knight, Richard
76cd0c41-511b-475a-af63-938b74ef8270
Gardin, Julius
99b66532-4c42-4e43-8e5d-0b89446e0ff9
Scarabelli, Tiziano M.
ac96a777-880e-4e39-9884-f11a0978da35
Stephanou, Anastasis
e9d502e8-693c-4458-a3c6-5e2844665db3
Pasini, Evasio
42f0e7e2-ef74-4f6f-bee7-ca2f8ce506d2
Gitti, Gianluca
5f875800-dad6-4405-aa76-2f3197788116
Townsend, Paul
54e7bb11-feba-4886-b792-ab0f93c9c734
Lawrence, Kevin
fe8c9942-70e6-48f7-bfe5-94b81105ec28
Chen-Scarabelli, Carol
bf53cd01-66c4-4d7e-859c-9da789e8ba49
Saravolatz, Louis
e7a9e7ec-3371-4087-9ed2-db267f3c1d44
Latchman, David
bb096dcc-99be-44a2-85f2-34b776de6abc
Knight, Richard
76cd0c41-511b-475a-af63-938b74ef8270
Gardin, Julius
99b66532-4c42-4e43-8e5d-0b89446e0ff9

Scarabelli, Tiziano M., Stephanou, Anastasis, Pasini, Evasio, Gitti, Gianluca, Townsend, Paul, Lawrence, Kevin, Chen-Scarabelli, Carol, Saravolatz, Louis, Latchman, David, Knight, Richard and Gardin, Julius (2004) Minocycline inhibits caspase activation and reactivation, increases the ratio of XIAP to smac/DIABLO, and reduces the mitochondrial leakage of cytochrome C and smac/DIABLO. Journal of the American College of Cardiology, 43 (5), 865-874. (doi:10.1016/j.jacc.2003.09.050).

Record type: Article

Abstract

Objectives: This study is aimed at investigating the novel use of minocycline for cardiac protection during ischemia/reperfusion (I/R) injury, as well as its mechanism of action.
Background: Minocycline is a tetracycline with anti-inflammatory properties, which is used clinically for the treatment of diseases such as urethritis and rheumatoid arthritis. Experimentally, minocycline has also been shown to be neuroprotective in animal models of cerebral ischemia and to delay progression and improve survival in mouse models of neurodegenerative diseases.
Methods: We studied 62 rat intact hearts exposed to I/R and cell cultures of neonatal and adult rat ventricular myocytes.
Results: Minocycline significantly reduced necrotic and apoptotic cell death, both in neonatal and adult myocytes, not only when given prior to hypoxia (p < 0.001), but also at reoxygenation (p < 0.05). Moreover, in the intact heart exposed to I/R, in vivo treatment with minocycline promoted hemodynamic recovery (p < 0.001) and cell survival, with reduction of infarct size (p < 0.001), cardiac release of creatine phosphokinase (p < 0.001), and apoptotic cell death (p < 0.001). In regard to its antiapoptotic mechanism of action, minocycline significantly reduced the expression level of initiator caspases, increased the ratio of XIAP to Smac/DIABLO at both the messenger RNA and protein level, and prevented mitochondrial release of cytochrome c and Smac/DIABLO (all, p < 0.05). These synergistic actions dramatically prevent the post-ischemic induction of caspase activity associated with cardiac I/R injury.
Conclusions: Because of its safety record and multiple novel mechanisms of action, minocycline may be a valuable cardioprotective agent to ameliorate cardiac dysfunction and cell loss associated with I/R injury.

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More information

Published date: March 2004
Keywords: reperfusion injury, survival, enzymology, animals, rats, heart, proteins, injuries, adult, myocardial infarction, cardiac, rheumatoid arthritis, cell survival, activity, sprague-dawley

Identifiers

Local EPrints ID: 60209
URI: https://eprints.soton.ac.uk/id/eprint/60209
ISSN: 0735-1097
PURE UUID: c9b46665-a113-468c-afcb-7ac618b2739a

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Date deposited: 08 Sep 2008
Last modified: 13 Mar 2019 20:29

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