PRECLINICAL INVESTIGATION
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
Tiziano M. Scarabelli, MD, PhD*,*,
Anastasis Stephanou, PhD ,
Evasio Pasini, MD ,
Gianluca Gitti, BSc,
Paul Townsend, PhD,
Kevin Lawrence, PhD,
Carol Chen-Scarabelli, MSc||,
Louis Saravolatz, MD ,
David Latchman, PhD, DSc,
Richard Knight, MD, PhD¶ and
Julius Gardin, MD*
* Division of Cardiology, Detroit, Michigan, USA
Division of Internal Medicine, St. John Hospital and Medical Center, Detroit, Michigan, USA
Institute of Child Health, University College London, London, England, UK
Cardiovascular Pathophysiology Research Centre, S. Maugeri Foundation, IRCCS Gussago, Italy
|| Division of Cardiovascular Surgery, Jackson Memorial Hospital, University of Miami, Miami, Florida, USA
¶ Department of Cystic Fibrosis, National Heart and Lung Institute, Imperial College London, London, England, , UK
Manuscript received May 19, 2003;
revised manuscript received July 25, 2003,
accepted September 8, 2003.
* Reprint requests and correspondence: Dr. Tiziano M. Scarabelli, Division of Cardiology, St. John Hospital and Medical Center, 22201 Moross Road, Detroit, Michigan 48236, USA.
tiziano.scarabelli{at}stjohn.org
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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Abbreviations and Acronyms
| | CPK | = creatine phosphokinase | | FP | = forward primer | | iNOS | = inducible form of nitric oxide synthase | | I/R | = ischemia/reperfusion | | LV | = left ventricle/ventricular | | LVEDP | = left ventricular end-diastolic pressure | | LVSP | = left ventricular systolic pressure | | PI | = propidium iodide | | RP | = reverse primer | | RT-PCR | = reverse transcription-polymerase chain reaction |
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