Cardiac reperfusion injury: Aging, lipid peroxidation, and mitochondrial dysfunction

Abstract

Cardiac reperfusion and aging are associated with increased rates of mitochondrial free radical production. Mitochondria are therefore a likely site of reperfusion-induced oxidative damage, the severity of which may increase with age. 4-Hydroxy-2-nonenal (HNE), a major product of lipid peroxidation, increases in concentration upon reperfusion of ischemic cardiac tissue, can react with and inactivate enzymes, and inhibits mitochondrial respiration in vitro. HNE modification of mitochondrial protein(s) might, therefore, be expected to occur during reperfusion and result in loss in mitochondrial function. In addition, this process may be more prevalent in aged animals. To begin to test this hypothesis, hearts from 8-and 24-month-old rats were perfused in Langendorff fashion and subjected to periods of ischemia and͞or reperfusion. The rate of state 3 respiration of mitochondria isolated from hearts exposed to ischemia (25 min) was approximately 25% less than that of controls, independent of age. Reperfusion (40 min) caused a further decline in the rate of state 3 respiration in hearts isolated from 24-but not 8-month-old rats. Furthermore, HNE modification of mitochondrial protein (ϳ30 and 44 kDa) occurred only during reperfusion of hearts from 24-month-old rats. Thus, HNE-modified protein was present in only those mitochondria exhibiting reperfusion-induced declines in function. These studies therefore identify mitochondria as a subcellular target of reperfusion damage and a site of age-related increases in susceptibility to injury.Oxygen free radicals increase in concentration upon reperfusion of ischemic cardiac tissue (1-11). It is well established that these reactive species can interact with and damage various cellular components (for review, see refs. 12-14). Thus, although restoration of blood flow is the sole method for salvaging ischemic tissue, oxidative damage may occur during reoxygenation and contribute to ischemia-reperfusion injury. Free radical production in the heart has also been reported to increase with age (15)(16)(17)(18)(19). Myocardium of senescent animals may, therefore, be more susceptible to reperfusion-induced oxidative damage. Cellular and subcellular targets of free radical damage and the mechanism and contribution of these events to myocardial ischemia-reperfusion injury have not, however, been established.Free radicals, such as hydroxyl radical, are highly reactive and short-lived species. They would therefore be expected to cause damage at or near the site of their formation. The mitochondrial respiratory chain represents a major subcellular source of free radical species during reperfusion of ischemic myocardium (20,21). In addition, myocardial ischemiareperfusion has been associated with decreased rates of NADH-linked state 3 (ADP-dependent) respiration (22-27). Of particular importance to this study, heart mitochondria isolated from senescent animals exhibit higher rates of oxygen radical production than those from young animals (15-19). Thus, mitochondria are a likely si...

Arterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease Enterprises

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Myocardial Protection in Neonates and Infants: What have we Learnt? Where do we Go?

“…Due to smaller body size, smaller hardware and prime solution volumes are required. There is relative abundance of PUFA (poly unsaturated fatty acids) in membranes of cellular and sub cellular organelles, providing additional sites of oxidative damage [19,20] and making the immature cyanotic heart more vulnerable to oxidative insult.…”

“…In the immature particularly cyanotic heart there is also an overproduction of oxygen free radical upon re-oxygenation. The implication of these differences is that a cyanotic heart is more prone to reperfusion injury not only after the release of aortic cross clamp but also on institution of cardiopulmonary bypass if hyperoxic bypass strategy is used [19,20,[24][25][26]. At the same time, there is also decreased 5` nucleotidase activity in the pediatric heart which results in a maintained nucleic acid pool which is essential for the recovery of energy debt when perfusion is resumed.…”

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“…Oxidative damage is therefore likely to play a role in the decline of mitochondrial function 6 . With aging, increased susceptibility to oxidative stress is known to lead to declined mitochondrial function, especially following an ischemic-reperfusion insult 5 . In this study we investigated the effects of aging on mitochondrial function in brain following cardiac arrest and resuscitation.…”