Ischemia/Reperfusion Injury following Acute Myocardial Infarction: A Critical Issue for Clinicians and Forensic Pathologists

Figure 2

Schematic representation of oxidative stress contributing to tissue injury and cell death in IRI. Following ischemia, hypoxia results in reduction of ATP production, ion pump function unbalance, leading to overload of Na⁺ and Ca²⁺, activation of anaerobic glycolysis, and, finally, reduction of pH. During the initial ischemic phase, the activation and upregulation of enzymes (such as NADPH oxidase, a superoxide-generating enzyme comprising a membrane-bound catalytic subunit) occurs, that are capable of producing ROS, when molecular oxygen is reintroduced in the reperfusion phase. ROS induces cell dysfunction and death via other mechanisms: activation of metalloproteinases and calpains, mitochondrial permeability transition pore (MPTP) opening which contributes to swelling and lysis of cells. This may elicit the release of proapoptotic factors in the cytosol, thus contributing to cell death. ROS indirectly interact with nitric oxide (NO) production, partly mediated by the inducible NOS (iNOS), the high-capacity NO-producing enzyme. Unlike the other two NOS isoforms, iNOS is not constitutively expressed in cells, and its production is elicited by several stimuli like IRI. NO cytotoxic effects are both direct and indirect mediated by NO reaction with superoxide to form the potent oxidant peroxynitrite which in turn exerts cytotoxicity.