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.
OBJECTIVE
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.
Division of Cardiology, Detroit, St John Hospital and Medical Center, Detroit, Michigan 48236, USA. tiziano.scarabelli@stjohn.org
Tiziano M
TM
Scarabelli
Anastasis
A
Stephanou
Evasio
E
Pasini
Gianluca
G
Gitti
Paul
P
Townsend
Kevin
K
Lawrence
Carol
C
Chen-Scarabelli
Louis
L
Saravolatz
David
D
Latchman
Richard
R
Knight
Julius
J
Gardin
D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009203:Myocardial Infarction / Q000201:enzymology; D017202:Myocardial Ischemia / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000008:administration & dosage; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology; D051636:X-Linked Inhibitor of Apoptosis Protein
D000900:Anti-Bacterial Agents; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C489013:DIABLO protein, rat; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D045304:Cytochromes c; D008911:Minocycline; D010100:Oxygen