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

• Published in: Journal of the American College of Cardiology 2004-03, Vol.43 (5), p.865-874
• Main Authors: Scarabelli, Tiziano M., Stephanou, Anastasis, Pasini, Evasio, Gitti, Gianluca, Townsend, Paul, Lawrence, Kevin, Chen-Scarabelli, Carol, Saravolatz, Louis, Latchman, David, Knight, Richard, Gardin, Julius
• Format: Article
• Language: English
• Subjects: Activation; Animal models; Animals; Animals, Newborn; Anti-Bacterial Agents - pharmacology; Anti-inflammatory agents; Antibiotics; Apoptosis; Arthritis; Biological and medical sciences; Cardiac muscle; Cardiology; Cardiology. Vascular system; Cardiomyocytes; Carrier Proteins - metabolism; Caspase; Caspase Inhibitors; Cell death; Cell survival; Cells, Cultured; Creatine; Creatine kinase; Cytochrome; Cytochrome c; Cytochromes; Cytochromes c - metabolism; DIABLO protein; Down-Regulation; Drug dosages; Enzyme Inhibitors - metabolism; Free radicals; Heart; Hemodynamics; Hypoxia; Inflammation; Injuries; Ischemia; Medical sciences; Medical treatment; Minocycline; Minocycline - pharmacology; Mitochondria; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Mitochondrial Proteins - metabolism; mRNA; Myocardial Infarction - enzymology; Myocardial Ischemia - enzymology; Myocytes; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Neonates; Neurodegenerative diseases; Neuroprotection; Oxygen - administration & dosage; Proteins; Proteins - metabolism; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury - enzymology; Rheumatoid arthritis; Ribonucleic acid; RNA; Rodents; Survival; Urethritis; Ventricle; X-Linked Inhibitor of Apoptosis Protein
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2003.09.050

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. 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. We studied 62 rat intact hearts exposed to I/R and cell cultures of neonatal and adult rat ventricular myocytes. 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. 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.