Sulforaphane protects from myocardial ischemia-reperfusion damage through the balanced activation of Nrf2/AhR.

The activation of the transcription factor Nrf2 and the consequent increment in the antioxidant response might be a powerful strategy to contend against reperfusion damage. In this study we compared the effectiveness between sulforaphane (SFN), a well known activator of Nrf2 and the mechanical maneuver of post-conditioning (PostC) to confer cardioprotection in an in vivo cardiac ischemia-reperfusion model. We also evaluated if additional mechanisms, besides Nrf2 activation contribute to cardioprotection. Our results showed that SFN exerts an enhanced protective response as compared to PostC. Bot, strategies preserved cardiac function, decreased infarct size, oxidative stress and inflammation, through common protective pathways; however, the aryl hydrocarbon receptor (AhR) also participated in the protection conferred by SFN. Our data suggest that SFN-mediated cardioprotection involves transient Nrf2 activation, followed by phase I enzymes upregulation at the end of reperfusion, as a long-term protection mechanism.

3-NP-induced Huntington's-like disease impairs Nrf2 activation without loss of cardiac function in aged rats.

Cardiovascular diseases (CVDs) are one of the leading causes of death in patients over 60years with Huntington's disease (HD). Here, we investigated if age-related oxidative stress (OS) is a relevant factor to develop cardiac damage in an in vivo model of striatal neurodegeneration induced by 3-nitropropionic acid (3-NP). We also evaluated the potential effect of tert-butylhydroquinone (tBHQ) to increase the Nrf2-regulated antioxidant response in hearts from adult and aged rats intoxicated with 3-NP. Our results showed that 3-NP-treatment did not induce cardiac dysfunction, neither in adult nor in aged rats. However, at the cellular level, adult animals showed higher susceptibility to 3-NP-induced damage than aged rats, which suggest that chronic oxidative stress ongoing during aging might have induced an hormetic response that probably prevented from further 3-NP damage. We also found that the oxidative unbalance concurs with unresponsiveness of the Nrf2-mediated antioxidant response in old animals.

Role of sphingomyelinase in mitochondrial ceramide accumulation during reperfusion.

Ceramide accumulation in mitochondria has been associated with reperfusion damage, but the underlying mechanisms are not clearly elucidated. In this work we investigate the role of sphingomyelinases in mitochondrial ceramide accumulation, its effect on reactive oxygen species production, as well as on mitochondrial function by using the sphingomyelinase inhibitor, tricyclodecan-9-yl-xanthogenate (D609). Correlation between neutral sphingomyelinase (nSMase) activity and changes in ceramide content were performed in whole tissue and in isolated mitochondria from reperfused hearts. Overall results demonstrated that D609 treatment attenuates cardiac dysfuncion, mitochondrial injury and oxidative stress. Ceramide was accumulated in mitochondria, but not in the microsomal fraction of the ischemic-reperfused (I/R) group. In close association, the activity of nSMase increased, whereas glutathione (GSH) levels diminished in mitochondria after reperfusion. On the other hand, reduction of ceramide levels in mitochondria from I/R+D609 hearts correlated with diminished nSMase activity, coupling of oxidative phosphorylation and with mitochondrial integrity maintenance. These results suggest that mitochondrial nSMase activity contributes to compartmentation and further accumulation of ceramide in mitochondria, deregulating their function during reperfusion.

Pharmacological strategies to contend against myocardial reperfusion damage: diverse chemicals for multiple targets.

Acute myocardial infarction is a frequent and disabling disease. Paradoxically, reperfusion, the most effective treatment to reduce infarct size, can both protect and kill. Although reperfusion protects by preventing lesions occurring during prolonged ischemia, it causes damage because reflow is associated with an unbalance between oxygen availability and metabolic demand, altered ionic homeostasis, and reactive oxygen species (ROS) generation. Recently, more players in myocardial reperfusion injury have been described: protein kinase C (PKC) and members of the MAP kinase, which activate downstream cascades that may activate intricate processes compromising cardiac recovery after ischemia. All together, such mechanisms promote endothelial and vascular dysfunction, sequels of impaired blood flow, metabolic and contractile dysfunction, dysrhythmia, cellular necrosis and apoptosis. Different pharmacological agents, as well as mechanical strategies, have been used to challenge the outcome of the complex interactions among these mechanisms and with others. In this review, we focused on the potential of different compounds used in animal models and in the clinical practice to improve the prognosis after post-ischemic reperfusion. We also review mechanisms activated during reperfusion injury and the structure-activity relationship between some of the cardioprotective chemicals and their cellular targets.