Cardiovascular Research

Cardiovascular Research 2002 55(3):466-473; doi:10.1016/S0008-6363(02)00277-8
© 2002 by European Society of Cardiology

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Copyright © 2002, European Society of Cardiology

Endothelial protective effects of preconditioning

Karine Laude, Philippe Beauchamp, Christian Thuillez and Vincent Richard^*

INSERM E9920, IFRMP 23, Department of Pharmacology, Faculté de Médecine, Rouen University, 22 Bd. Gambetta, 76183 Rouen CEDEX 1, France

^* Corresponding author. Tel.: +33-2-3514-8362; fax: +33-2-3514-8365 vincent.richard{at}univ-rouen.fr

Received 2 November 2001; accepted 21 January 2002

	Abstract

Top Abstract 1 Introduction 2 'Classic' preconditioning of... 3 Delayed endothelial... 4 Conclusions References

 
The consequences of cardiac ischemia–reperfusion are not limited to myocytes but also extend to the coronary endothelium, where they are characterized by decreased nitric oxide (NO)-dependent relaxations. Given the essential role of the endothelium and NO in the regulation of vascular tone as well as platelet and leukocyte function, protection of coronary endothelial cells is an important therapeutic target. In this context, several studies have shown that both early and delayed preconditioning may prevent endothelial dysfunction after index ischemia–reperfusion. This endothelial protection most likely results from the inhibitory effects of preconditioning on expression of endothelial adhesion molecules, resulting in reduced neutrophil–endothelial interactions. The mechanisms of early endothelial preconditioning resemble those described at the level of the myocytes, and may involve mediators such as adenosine, bradykinin, NO and free radicals, together with activation of protein kinase C and opening of ATP-sensitive potassium channels. With regard to delayed preconditioning, recent studies have shown that both NO and free radicals are involved as triggers of this second window of endothelial protection. The complex interactions between these two radical species ultimately lead to a delayed increase in NO production, most likely responsible for the decreased adhesion of neutrophils to endothelial cells. Further identification of the triggers and mediators of this endothelial protection will allow the development of new therapeutic agents targeting both the myocardium and the coronary vasculature.

KEYWORDS Endothelial function; Free radicals; Ischemia; Nitric oxide; Preconditioning; Reperfusion

	1 Introduction

Top Abstract 1 Introduction 2 'Classic' preconditioning of... 3 Delayed endothelial... 4 Conclusions References

 
Although cardiac ischemia–reperfusion is well known as a disease of myocytes, it is now clear that its consequences also extend to the vascular wall and especially to endothelial cells. Indeed, myocardial ischemia and reperfusion induce marked structural injury to endothelial cells [1], accompanied by decreased endothelium-dependent relaxations of isolated large or medium size coronary arteries to thrombin [2] or acetylcholine [3]. However, the response to endothelium-independent vasodilators such as nitroprusside is intact. Thus, myocardial ischemia–reperfusion is associated with an altered nitric oxide (NO)-dependent relaxation of conduit coronary arteries. This endothelial dysfunction is not a transient phenomenon, since it may persist several months after reperfusion [1,4].

Several studies have investigated the mechanisms of endothelial injury. One major finding is that it does not occur after ischemia without reperfusion [5], suggesting that it is essentially a manifestation of reperfusion injury. Moreover, it has been observed that the endothelial injury can be attenuated by scavengers of reactive oxygen species [6]. Indeed, superoxide anions produced at reperfusion are potent inactivators of NO [7,8]. Since NO is an inhibitor of neutrophil activation and adhesion [9], the decreased NO production may lead to the development of an acute inflammatory response. Moreover, since free radicals also trigger the rapid adhesion of neutrophils to endothelial cells through the induction of adhesion molecules [10], the combined effects of the decreased production of NO and the increased production of free radicals will reinforce the adhesion of neutrophils to endothelial cells, setting the stage for an amplification of the neutrophil-mediated endothelial injury.

The pathophysiological significance of reperfusion-induced coronary endothelial injury of large coronary arteries may be related, at least in part, to the properties of endothelium-derived NO at this level. Indeed, constitutive NO production continuously opposes vasoconstrictor influences in large coronary arteries [11]. Moreover, NO, as well as other endothelium-derived factors such as prostacyclin, is an inhibitor of platelet aggregation [12]. Thus, endothelial dysfunction may lead to an increased coronary vasoconstriction and an increased platelet aggregation, leading to subsequent increased risk of vasospasm and thrombosis, respectively. Moreover, the inhibitory effects of NO on leukocyte activation and adhesion suggest that endothelial dysfunction is one of the triggering factors for local vascular inflammatory responses which lead to the development of atherosclerosis [13].

These important consequences of reperfusion-induced coronary endothelial injury indicate that prevention of endothelial dysfunction of large coronary arteries after reperfusion is an important therapeutic goal.

The most potent anti-ischemic intervention known to date is the endogenous protection of ischemic myocardium, first described by Murry et al. [14] in 1986, and termed ‘preconditioning’. According to these experiments, submitting the heart to short episodes of ischemia separated by intermittent reperfusion renders it more resistant to subsequent, more prolonged (or ‘index’) ischemia and markedly limits infarct size. Two phases of preconditioning have been described: an early phase (‘classic’ preconditioning), for which the protection is lost if the time interval between the preconditioning stimulus and the more prolonged period of ischemia is increased from several minutes to about 2–3 h [15], and a late phase (delayed preconditioning, or second window of protection) which appears 12–24 h after the stimulus [16–18]. Although most of the studies on preconditioning have concentrated on its capacity to protect the cardiac myocytes, there is also some evidence that preconditioning may also protect the coronary vasculature, and especially endothelial cells. The present review summarizes current knowledge on endothelial protection against prolonged ischemia–reperfusion injury by preconditioning, especially focusing on large coronary arteries.

	2 ‘Classic’ preconditioning of endothelial cells

Top Abstract 1 Introduction 2 'Classic' preconditioning of... 3 Delayed endothelial... 4 Conclusions References

 
2.1 Evidence
The potential endothelial protective effects of ‘classic’ (or early) preconditioning have been mostly assessed in the rat. For example, our group developed a rat model of myocardial infarction in which animals are subjected to index ischemia (20 min) followed by reperfusion (60 min), immediately after a sham surgery or preconditioning (1 cycle of 2 min ischemia/5 min reperfusion, followed by 2 cycles of 5 min ischemia/5 min reperfusion). At the end of reperfusion, hearts were removed and coronary artery segments were taken distal to the site of occlusion and mounted in small vessel wire myographs to study their reactivity in the presence of vasoactive agents, and especially the NO-dependent relaxations to acetylcholine. In this context, index ischemia followed by reperfusion impaired the ability of acetylcholine to cause an endothelium-dependent relaxation (Fig. 1). Preconditioning reduced this impairment [1,5]. In parallel, the fact that preconditioning also prevented structural endothelial injury evaluated by electron microscopy [1] suggests that the observed functional improvement (evaluated as the improved response to acetylcholine) most likely reflects protective effects of preconditioning against reperfusion-induced endothelial injury and endothelial cell death.

View larger version (21K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Prevention of reperfusion-induced coronary endothelial dysfunction by preconditioning (PC). Bars show the relaxations induced by 3x10–5 M acetylcholine in coronary artery segments isolated from sham rats, rats subjected to index ischemia without or with reperfusion, or rats subjected to index ischemia followed by reperfusion 5 min (early PC) or 24 h after PC (delayed PC). Ischemia–reperfusion markedly reduced the response to acetylcholine, whereas ischemia alone had no effect. The reperfusion-induced impairment in the response to acetylcholine was reversed both by early and delayed preconditioning. * P<0.05 vs. sham; P<0.05 vs. I/R. Redrawn from results obtained in Refs. [5,6], and [34] with permission.

 
These results demonstrated that early preconditioning protects the endothelium of large epicardial or medium size intramyocardial coronary arteries against reperfusion injury. Such protection, involving arteries which do not markedly contribute to coronary resistance, most likely has little consequences in terms of tissue perfusion (at least in the absence of coronary stenosis) or cardioprotection. However, the fact that preconditioning induced an early and sustained improvement of endothelial function at the level of conduit coronary arteries after reperfusion may have immediate effects, for example, through prevention of neutrophil-mediated injury, but also long term consequences, for example, by preventing the increased risks of vasospasm, thrombosis and atherosclerosis, ultimately leading to a reduced risk of (re)infarction.

It must be also noted that a transient endothelial dysfunction may occur following the preconditioning stimulus. Indeed, it has been demonstrated that a 15-min period of ischemia was associated with a severe impairment of the endothelium-dependent response of canine coronary arteries to acetylcholine or bradykinin which was present during the first hour of reperfusion but gradually recovered after 90–120 min [19]. This functional impairment was not associated with endothelial structural damage, suggesting the existence of a stunning of endothelium. Such an ‘endothelial stunning’ was also observed after multiple brief coronary occlusions [20].

Several studies also assessed the protective role of preconditioning at the level of the coronary microcirculation [21,22]. In isolated perfused rat or guinea-pig hearts, preconditioning preserved the coronary response to endothelium-dependent vasodilators after global low-flow ischemia followed by reperfusion [22,23]. It must be noted, however, that the evaluation of the effect of preconditioning on the coronary microcirculation in intact hearts is rendered difficult by the possible interference with smooth muscle cell injury and with the extent of necrosis (for example, through changes in extravascular compression and edema). In the case of preconditioning, it is difficult to separate the potential direct endothelial protective effects from its indirect effects, secondary to the marked limitation of infarct size it induces. However, the fact that microvascular endothelial cells may be directly preconditioned is supported by the data of Zhou et al. [24] who showed that preconditioning protects cultured bovine microcirculatory endothelial cells against reoxygenation injury and cell death.

One important aspect of endothelial preconditioning is that it may be induced in humans, although this has not yet been tested in the coronary circulation. Indeed, endothelial preconditioning may be evidenced at the level of the human peripheral circulation in vivo [25], where preconditioning prevents both the impaired flow-mediated vasodilatation of the radial artery and the impaired forearm vasodilatory response to acetylcholine after prolonged forearm ischemia in healthy volunteers. This suggests that preconditioning protects human endothelial cells both at the level of large conduit arteries and that of the microcirculation [25].

2.2 Mechanisms
Given the essential role of neutrophil adhesion in the development of reperfusion injury to the endothelium, it is likely that preconditioning protects endothelial cells partly through a decreased adhesion of neutrophils, secondary to a decreased production of endothelial adhesion molecules. To test this hypothesis, we subjected cultured endothelial cells to prolonged anoxia/reoxygenation in vitro, and preconditioned the cells with a brief sequence of anoxia/reoxygenation [26]. In this context, preconditioning reduced the adhesion of neutrophils to the reoxygenated endothelium, and abolished the increased intercellular adhesion molecule-1 (ICAM-1) mRNA expression and protein levels observed during reoxygenation after prolonged anoxia. The increased adhesion and expression of ICAM-1 may also be prevented by free radical scavengers, suggesting that it is mediated by free radicals. These results suggest that preconditioning may protect endothelial cells from neutrophil-mediated free radical injury during reperfusion. This hypothesis is also supported by experiments showing a reduced neutrophil activation after preconditioning in the human forearm [25], as well as in various animals models [27–29].

2.3 Mediators
The mediators of ‘classic’ endothelial preconditioning have also been evaluated in some studies (Fig. 2), mainly in isolated rat hearts and in cultured cells. Most of these studies evaluated the role of mediators known to participate to the cardioprotective effect of preconditioning. Indeed, adenosine participates to endothelial preconditioning in isolated rat hearts [22] and in a cultured bovine microvascular cell line [24], although no role of adenosine is observed in a primary culture of rat aortic endothelial cells [26]. Studies in isolated rat hearts also suggest a potential role of kinins (through activation of B1 receptors [30]) and prostaglandin E2 [31] in endothelial preconditioning. Similar to myocytes [32], endothelial preconditioning appears to involve activation of protein kinase C [24,26] and possibly opening of ATP-sensitive potassium channels [22,23]. Finally, in cultured endothelial cells, the inhibitory effect of preconditioning on ICAM-1 expression is abolished by free radical scavengers and NO synthase inhibitors administered during preconditioning [26], suggesting that it requires both NO and free radicals. Thus, based on these findings and on current knowledge on the cardioprotective effects of preconditioning, it appears that early endothelial preconditioning may involve a series of mediators such as adenosine, kinins, prostaglandins, NO and reactive oxygen species, which activate protein kinase C and trigger the opening of ATP-sensitive potassium channel, leading to reduced endothelial–neutrophil interactions and ultimately to endothelial protection (Fig. 2). However, it must be noted that this full sequence of events so far has not been tested in a single experimental model, and thus still remains theoretical. Moreover, it is also possible that the exact mediators of endothelial preconditioning differ from those of myocardial preconditioning.

View larger version (23K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Proposed mechanisms of early (or ‘classic’) preconditioning.

 

	3 Delayed endothelial preconditioning

Top Abstract 1 Introduction 2 'Classic' preconditioning of... 3 Delayed endothelial... 4 Conclusions References

 
Although ‘classic’ preconditioning has efficient cardioprotective effects, this protection is transient, and disappears if the period of reperfusion separating preconditioning from index ischemia extends over 2–3 h [15]. This time course possibly limits its therapeutic application. However, myocardial protection reappears several hours after preconditioning. Indeed, preconditioning performed 24 h before prolonged coronary occlusion is associated with a significant limitation of infarct size in dogs [16], or in rabbits [17,18], as well as a prevention of myocardial stunning [18,33]. However, at present, only very few studies assessed whether such a ‘second window’ of protection exists at the level of coronary endothelial cells.

3.1 Evidence of delayed endothelial preconditioning
To test the hypothesis that the cardioprotective effects of delayed preconditioning extend to coronary endothelial cells, we subjected anesthetized rats to three periods of intermittent left coronary artery occlusion. Twenty-four hours later, rats were re-anesthetized and subjected to the standard ischemia–reperfusion protocol described above [1,5]. These experiments showed that, in addition to having beneficial effects on infarct size and postischemic myocardial contractile dysfunction, delayed preconditioning also protects endothelial cells of conduit coronary arteries against ischemia–reperfusion injury [6,34] (Fig. 1). In the same model, we also showed that heat stress, which induces cardioprotection by mechanisms similar to those of delayed preconditioning, also completely prevents reperfusion-induced endothelial dysfunction [35]. Delayed endothelial protection could also be demonstrated with the preconditioning mimetic monophosphoryl lipid A [36].

To the best of our knowledge, the effects of delayed preconditioning per se on endothelial cells from the coronary microcirculation have not been evaluated. However, heat stress has been shown to induce delayed endothelial protection in isolated rat hearts subjected to low-flow ischemia [37].

The effects of delayed preconditioning have also been examined in cultured aortic endothelial cells, where preconditioning with a 1-h period of anoxia followed by reoxygenation 24 h before a prolonged (6 h) period of anoxia abolished the increased adhesion of neutrophils upon reoxygenation, as well as the increased expression of ICAM-1 mRNA [38]. This suggests that, similar to early preconditioning, the endothelial protective effects of delayed preconditioning involve a decreased adhesion of neutrophils to endothelial cells. However, so far this has not been tested in in vivo models of ischemia–reperfusion.

Examination of the mechanisms involved in delayed preconditioning has to be separated in two parts: (1) the ‘triggering phase’, during which molecular species generated during brief ischemia and reperfusion are responsible for the initiation of the protection, and (2) the ‘mediating phase’, which corresponds to the production of molecular species 24 h after preconditioning, which confer protection.

3.2 Triggers
The role of NO as a trigger of delayed endothelial preconditioning was assessed in our experiments with the use of the nonselective NOS inhibitor N^G-nitro-L-arginine methyl ester (L-NAME) and the selective inducible NOS (iNOS) inhibitor N-(3(aminomethyl)benzyl)acetaminide (1400W) administered before preconditioning. In this context, L-NAME completely abolished the protective effect of delayed preconditioning against coronary endothelial injury, while 1400W had no effect [39]. These results suggest that NO acts as a trigger of delayed preconditioning at the level of endothelial cells, through its production by a constitutive NOS (most likely eNOS).

Such an involvement of NO as a trigger of delayed preconditioning has been previously observed in the protection against myocardial stunning [40] and infarction [41]. Moreover, NO donors can mimic these effects [42], supporting the possibility of novel clinical implications of these drugs. Thus, NO, likely produced by eNOS, seems to be a common trigger of delayed preconditioning, both at the level of myocardium and coronary endothelium.

Interestingly, the delayed endothelial effects of preconditioning may also be abolished by administration of free radical scavengers [6], suggesting that free radicals also are essential triggers of late preconditioning. These results raise the interesting hypothesis that reactive oxygen species may serve as a signaling molecule at low concentration, leading to the delayed adaptation of endothelial cells against reperfusion injury [43].

The fact that both NO and free radicals are essential for the induction of endothelial preconditioning suggests that NO reacts with free radicals to form other intermediates, such as peroxynitrites [44,45] that trigger the delayed protection. However, the role of peroxynitrites or possibly of other intermediates of the reaction between NO and free radicals as trigger of delayed preconditioning has not been yet demonstrated.

3.3 Mediators
The time course of the development of delayed preconditioning (i.e. 12–24 h) suggests that the protection involves the synthesis of new protective proteins. This is supported by experiments performed in a rabbit model of myocardial stunning where it has been shown that preconditioning has been completely abolished by the protein synthesis inhibitor, cycloheximide [46], although the role of protein synthesis has not been evaluated at the level of the endothelium.

One possibility by which delayed preconditioning induces endothelial protection is through an increase in NO production during index ischemia/reperfusion. Indeed, as mentioned above, index ischemia–reperfusion is mainly characterized by a decreased NO production and an increased free radical generation, leading to an increased neutrophil adhesion to the coronary endothelium. Moreover, exogenous administration of NO donors or stimulation of its endogenous production during ischemia–reperfusion prevents coronary endothelial injury [47,48]. Importantly, in chronically instrumented dogs, brief ischemia induces a delayed increase in the coronary flow response to two endothelium-dependent vasodilators, acetylcholine and bradykinin, together with an increased production of NO [49].

Support for a role of NO as a mediator of preconditioning also comes from results on the effects of delayed preconditioning on infarct size and myocardial stunning, which are abolished by selective iNOS inhibitors [50,51] or targeted disruption of the iNOS gene [52], suggesting a role for iNOS in this protection. However, we found that selective inhibition of iNOS by 1400W administered immediately before index ischemia (i.e. 24 h after preconditioning) did not affect endothelial protection, excluding a role for iNOS in delayed endothelial protection [34]. Such a dissociation between the involvement of iNOS as a mediator of delayed endothelial preconditioning at the level of the myocardium and the endothelium has also been observed after MLA-induced protection. Thus, although NO produced by iNOS was involved in the protection against infarction [53,54], the endothelial protective effects of delayed preconditioning were not modified after iNOS inhibition [36]. The observed differences may be linked to the properties of NO at the level of both cell types. An increased NO production at the level of the cardiomyocytes is mainly protective through a decreased contractility and a subsequent decrease in metabolic requirements, and may explain the involvement of iNOS rather than that of eNOS. Conversely, the endothelial effects of iNOS induction are linked to the concentration of NO produced. A moderate NO release after preconditioning may have protective effects on endothelial function. On the other hand, a higher production of NO may have deleterious effects on coronary endothelium. Indeed, NO reacts with free radicals to generate peroxynitrite and hydroxyl radicals. Such deleterious effects are not consistent with an endothelial protection by preconditioning, and may explain the absence of effect of iNOS inhibition in endothelial preconditioning.

In contrast to the lack of effect of iNOS inhibitors, the nonselective NOS inhibitor L-NAME abolished the endothelial protective effect of preconditioning [55]. This suggests that NO produced by constitutive NOS (most likely eNOS) is involved as a mediator of delayed coronary preconditioning. One possibility to explain the involvement of NO in delayed endothelial preconditioning would be that preconditioning induces a delayed increase in the bioavailability of NO, through a reduction of its degradation by free radicals. Such a lesser production of free radicals, leading to increased NO bioavailability, may be the consequence of an increased expression of antioxidant enzymes. Indeed, induction of superoxide dismutase (SOD) has been detected in rat hearts 24 h after preconditioning [56], adenosine [57] or heat stress [58], as well as in neonatal cardiomyocytes subjected to hypoxia [59]. Thus, it seems possible that the increased Mn-SOD mRNA and subsequent increased activity contribute to the protective effect of delayed endothelial preconditioning by decreasing free radical generation during reperfusion.

Although studies concerning the mechanisms of delayed endothelial preconditioning have mainly focused on the interactions between NO and free radicals, other molecules such as heat shock proteins (HSP) are of interest. Indeed, as mentioned above, heat stress (which triggers the expression of HSP), induces a delayed endothelial protection similar to preconditioning [35,37]. Moreover, endothelial cells express HSP70 in response to oxidative stress [60], and overexpression of HSP70 by gene transfection enhance the hypoxic tolerance of coronary endothelial cells [61]. These results suggest a protective role of HSP in endothelial cells, but whether this contributes to endothelial preconditioning is still unknown. It should also be noted that heat stress increases NO-dependent relaxations in rat arteries in the absence of ischemia [62], suggesting that the endothelial effects of heat stress may also be mediated by NO.

3.4 Possible mechanisms of delayed endothelial preconditioning
Based on the various observations summarized above, a general mechanism for the delayed endothelial protective effects of preconditioning may be advanced (Fig. 3). Indeed, brief periods of ischemia–reperfusion most likely trigger the generation of low levels of free radicals which interact with NO to form intermediate species (possibly peroxynitrites). These intermediates may then trigger a cascade of signaling events, probably including activation of transcription factors, that later induce gene expression of ‘protective’ proteins, such as NO synthases or antioxidant enzymes. This leads to a decreased oxidative stress and decreased inflammatory response during reperfusion after index ischemia, ultimately leading to endothelial protection.

View larger version (21K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Proposed mechanisms of delayed endothelial preconditioning.

 

	4 Conclusions

Top Abstract 1 Introduction 2 'Classic' preconditioning of... 3 Delayed endothelial... 4 Conclusions References

 
There is now large evidence that the protective effects of both early and delayed preconditioning extend to endothelial cells. Given the various known roles of these cells, such a protection may translate into better perfusion, but also into decreased risks of vasospasm, platelet aggregation, atherosclerosis and ultimately (re)infarction. Further identification of the mechanisms responsible for this endogenous protective effect may lead to the development of new pharmacological interventions which protect the endothelium during reperfusion, but also in other disease states characterized by an increased oxidative stress, such as hypertension [63], hypercholesterolemia or atherosclerosis [64].

Time for primary review 25 days.

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