Pleiotropic properties of minocycline preserve cardiac function during ischemia/reperfusion injury

Abstract

Minocycline, a broad‐spectrum antibiotic, has been reported to exhibit pleiotropic properties that yield protective effects in the setting of cardiac and brain ischemia/reperfusion (I/R) injury. We used in vitro and ex vivo cardiac systems to further explore the mechanisms involved in mediating cardioprotection. In vitro assays indicate minocycline bears comparable levels of antioxidant activity to those of the vitamin E analog Trolox. Recombinant enzyme assays indicate that minocycline acts as a matrix metalloproteinase (MMP) inhibitor with an IC50 of 118μM for MMP‐7 and 134μM for MMP‐9. Minocycline was tested ex vivo to assess recovery of cardiac function in stunned myocardium. Rate pressure product results indicated that 500nM minocycline conferred an average of 50% sustained recovery of contractile function vs. controls. It improves 25% vascular function and also suppresses 85% the release of troponin I vs. controls. We found that cultured cardiac fibroblasts and myocytes display a temperature‐ and time‐dependent active transport mechanism for minocycline uptake. In rats, the concentration of minocycline in normal myocardium is 0.6‐fold higher vs. serum. Furthermore, the concentration in I/R myocardium is 3.5‐fold higher compared to a non‐ischemic portion of the same heart. Altogether these results indicate that the high concentration of minocycline observed inside cardiac cells may allow it to act in a pleiotropic fashion to confer protection from I/R injury. Supported by NIH HL‐43617 and 67922.