Fig. 15.

Schematic diagram of DOX-induced cardiotoxicity: role of superoxide, NO, and peroxynitrite. DOX initially increases mitochondrial superoxide and, consequently, the generation of other ROS (e.g., H₂O₂) in cardiomyocytes and/or endothelial cells by redox cycling. Increased DOX-induced ROS generation in cardiomyocytes triggers the activation of the transcription factor NF-κB, leading to enhanced iNOS expression and NO generation. NO reacts with superoxide to form peroxynitrite both in the cytosol and mitochondria, which, in turn, induces cell damage via lipid peroxidation, inactivation of enzymes and other proteins by oxidation and nitration, and activation of stress signaling pathways (e.g., MAPK), MMPs, and PARP-1, among others. In the mitochondria, peroxynitrite, in concert with other ROS/reactive nitrogen species, impairs various key mitochondrial enzymes, leading to more sustained intracellular ROS generation (persistent even after DOX already metabolized), triggering further activation of transcription factor(s) and iNOS expression, resulting in the amplification of oxidative/nitrosative stress. In the mitochondria, peroxynitrite also triggers the release of proapoptotic factors (e.g., Cyt-C and apoptosis-inducing factor) mediating caspase-dependent and -independent cell death pathways, which are also pivotal in DOX-induced cardiotoxicity. Peroxynitrite, in concert with other oxidants, also causes strand breaks in DNA, activating the nuclear enzyme PARP-1. Once excessive oxidative and nitrosative stress-induced DNA damage occurs, overactivated PARP initiates an energy-consuming cycle by transferring ADP-ribose units from NAD⁺ to nuclear proteins, resulting in the rapid depletion of intracellular NAD⁺ and ATP pools, slowing the rate of glycolysis and mitochondrial respiration, eventually leading to cellular dysfunction and death, mostly by necrosis. Overactivated PARP may also facilitate the expression of a variety of inflammatory genes leading to increased inflammation (PARP-1 is a known coactivator of NF-κB) and associated oxidative stress, thus facilitating the progression of cardiovascular dysfunction and heart failure. PARG, poly(ADP-ribose) glycohydrolase.