Abstract
Excessive levels of reactive oxygen species (ROS) and impaired Ca2+ homeostasis play central roles in the development of multiple cardiac pathologies, including cell death during ischemia-reperfusion (I/R) injury. In several organs, treatment with 2-aminoethoxydiphenyl borate (2-APB) was shown to have protective effects, generally believed to be due to Ca2+ channel inhibition. However, the mechanism of 2-APB-induced cardioprotection has not been fully investigated. Herein we investigated the protective effects of 2-APB treatment against cardiac pathogenesis and deciphered the underlying mechanisms. In neonatal rat cardiomyocytes, treatment with 2-APB was shown to prevent hydrogen peroxide (H2O2) -induced cell death by inhibiting the increase in intracellular Ca2+ levels. However, no 2-APB-sensitive channel blocker inhibited H2O2-induced cell death and a direct reaction between 2-APB and H2O2 was detected by 1H-NMR, suggesting that 2-APB chemically scavenges extracellular ROS and provides cytoprotection. In a mouse I/R model, treatment with 2-APB led to a considerable reduction in the infarct size after I/R, which was accompanied by the reduction in ROS levels and neutrophil infiltration, indicating that the anti-oxidative properties of 2-APB plays an important role in the prevention of I/R injury in vivo as well. Taken together, present results indicate that 2-APB treatment induces cardioprotection and prevents ROS-induced cardiomyocyte death, at least partially, by the direct scavenging of extracellular ROS. Therefore, administration of 2-APB may represent a promising therapeutic strategy for the treatment of ROS-related cardiac pathology including I/R injury.
Highlights
Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide
To determine whether the increase of Ca2+ levels is due to the extracellular Ca2+ entry, EDTA was used for the removal of the extracellular Ca2+, and intracellular Ca2+ levels were assessed during H2O2 treatment
We demonstrated that treatment with 2-aminoethoxydiphenyl borate (2-APB) prevents reactive oxygen species (ROS)-induced cardiomyocyte death by inhibiting Ca2+ overload caused by an extracellular Ca2+ influx and attenuates cardiac I/R injury in mice
Summary
Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. One of the most dominant causes of death by CVD is myocardial infarction (MI), which is accompanied by massive cardiomyocyte death. Whereas the mechanisms underlying I/R injury and myocardial protection have been intensively investigated during the last three decades [2, 3], the clinical efficacy of few pharmacological therapies have been demonstrated [4]. Animal model research indicated that the overproduction of ROS may be responsible for I/R injury [10, 11], but the results of clinical studies with the administration of antioxidant therapy at the onset of myocardial reperfusion have been mixed [12]. Further mechanisms underlying cardiac I/R or novel tools for the regulation of ROS should be investigated
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