Abstract
Ischemic heart disease is a leading cause of death worldwide. Primarily, ischemia causes decreased oxygen supply, resulting in damage of the cardiac tissue. Naturally, reoxygenation has been recognized as the treatment of choice to recover blood flow through primary percutaneous coronary intervention. This treatment is the gold standard therapy to restore blood flow, but paradoxically it can also induce tissue injury. A number of different studies in animal models of acute myocardial infarction (AMI) suggest that ischemia-reperfusion injury (IRI) accounts for up to 50% of the final myocardial infarct size. Oxidative stress plays a critical role in the pathological process. Iron is an essential mineral required for a variety of vital biological functions but also has potentially toxic effects. A detrimental process induced by free iron is ferroptosis, a non-apoptotic type of programmed cell death. Accordingly, efforts to prevent ferroptosis in pathological settings have focused on the use of radical trapping antioxidants (RTAs), such as liproxstatin-1 (Lip-1). Hence, it is necessary to develop novel strategies to prevent cardiac IRI, thus improving the clinical outcome in patients with ischemic heart disease. The present review analyses the role of ferroptosis inhibition to prevent heart IRI, with special reference to Lip-1 as a promising drug in this clinicopathological context.
Highlights
Cardiovascular diseases are major causes of death and disability, reaching 17.9 million deaths in 2016 [1], among which ischemic heart disease is the leading cause of death along with stroke, respectively accounting for 16% and 11% of the total deaths worldwide [2].This represents an estimated total cost of 196,000 million euros per year in cardiovascular disease in Europe, approximately 54% of the total investment in health, and corresponds to a 24% loss of productivity [3]
10 reactive oxygen species (ROS) production sites have been described in the isolated rat skeletal muscle mitochondria, which correspond to sites Of, Pf, Bf, Af ubicated in the 2-oxoacid dehydrogenases complexes, sites If and IQ ubicated in complex I, IIIQo ubicated in complex III and the sites IIf, GQ, Ef and DQ are linked to the Q-dependet dehydrogenases in the QH2 /Q
In non-apoptotic cell death we can highlight ferroptosis, a regulated forms of necrosis that is caused by the accumulation of lipid peroxidation products and ROS derived from iron metabolism, mainly when GSH levels in the cell are depleted or when glutathione peroxidase 4 (GPX4) enzyme is inhibited [70]
Summary
Cardiovascular diseases are major causes of death and disability, reaching 17.9 million deaths in 2016 [1], among which ischemic heart disease is the leading cause of death along with stroke, respectively accounting for 16% and 11% of the total deaths worldwide [2]. It has been shown that the most effective interventions to reduce the infarct size and improve the clinical outcome are thrombolytic therapy and percutaneous coronary angioplasty aimed at restoring blood flow Paradoxically the latter can induce the death of cardiomyocytes and increase the infarct size, thereby reducing its beneficial effects. A number of studies have demonstrated that oxidative and nitrosative stress are leading causes of IRI, prompted by increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the process of ischemia followed by reperfusion. Another important contribution derives from the deregulation of iron homeostasis, which causes an increase in the myocardial intracellular free iron. The present review describes the cellular and molecular mechanisms related to oxidative stress induced by ischemia-reperfusion and deregulation of iron homeostasis, focused on the essential role of inhibition of ferroptosis to prevent IRI and the role of liproxstatin-1 as a promising drug in the treatment of this clinicopathological condition
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