Insulin: An overall cardiovascular protector?

See article by Ma et al.[4](pages 57–65) in this issue. Protection of myocardium against lethal reperfusion injury is one of the major challenges of clinical cardiology today. Many interventions during reperfusion that may influence infarct size or improve cardiac function have been studied experimentally, but none of these has yet found its way into clinical practice. One of the oldest and most discussed interventions to modify reperfusion conditions is the use of glucose–insulin–potassium (GIK) [1], which was reported to reduce the relative in-hospital mortality risk in patients with acute myocardial infarction [2]. Administration of insulin in vivo was shown to reduce reperfusion-induced cell death through a signalling pathway comprising PI 3-kinase (PI3K)/Akt and nitric oxide synthase (eNOS) [3]. The experimental study by Ma et al. [4] in this issue of Cardiovascular Research provides an interesting contribution, focusing for the first time on the role of GIK and particularly its leading actor, insulin, for prevention of reperfusion-induced vascular injury in the heart. Various mechanisms contributing to cardiac reperfusion injury have been described, but protective strategies share ultimately the same goal, i.e., prevention of cell death and improvement of cardiac function. On the level of cardiac myocytes, necrotic cell death has been described as an early cause of reperfusion injury [5], but apoptosis may also contribute to cell death later during reperfusion [6]. Investigations of our own group have demonstrated the occurrence of contracture of cardiac myocytes in the early minutes of reperfusion [7,8]. Contracture development is triggered by energy recovery at still elevated cytosolic calcium levels that result from preceding ischemia. This excessive contraction of cardiac myocytes is able to induce a rapid onset of tissue necrosis [9]. A temporary pharmacological blockade of the contractile apparatus at the onset of reperfusion was shown to markedly reduce infarct size in vivo [10]. On the vascular level, vascular dysfunction in reperfused myocardial tissue was described two decades ago [11] and was attributed to structural injury of endothelial cells [12]. Adhesion of neutrophils to endothelial cells was reported to play a major role. Generation of reactive oxygen species during reperfusion is thought to trigger a death cascade, implying the expression of adhesion molecules on endothelial cell surface and the reduced production or inactivation of nitric oxide, which normally serves as a potent inhibitor of neutrophil adhesion [13]. Immunohistochemical analysis of reperfused myocardium has shown that apoptosis of endothelial cells occurs in the early phase of reperfusion and precedes apoptosis of cardiac myocytes [14]. In various experimental studies, the PI3K/Akt signalling pathway has been identified to confer protection against reperfusion injury of the heart. It has therefore been termed a “survival pathway” [15]. This survival pathway is known to mediate cardioprotection achieved by insulin and also during the application of postconditioning, i.e. protection achieved by repetitive brief periods of ischemia applied within the first minutes of reperfusion [16]. On the one hand, activation of this signalling cascade was found to inactivate a variety of pro-apoptotic proteins such as Bad, BAX, BIM and p53 [17,18]. On the other hand, the PI3K/Akt pathway is able to activate eNOS by its phosphorylation and thus to augment the generation of NO [19]. NO was found to reduce infarct size dose-dependently when administered early during reperfusion [20] and may thus reduce acute development of necrotic cell injury. NO activates soluble guanylyl cyclase and thereby activates cGMP-dependent signalling. It has been shown that agents acting through cGMP-dependent pathways during reperfusion reduce infarct size in intact hearts [21] and attenuate hypercontracture in cardiac myocytes [22]. In these cells, the cellular mechanism of cGMP-mediated protection is likely related to the control of cytosolic calcium levels by the sarcoplasmic reticulum through an activation of the SR Ca2+ pump during the first few minutes of reperfusion [22]. The current study [4] demonstrates the ability of insulin to reduce reperfusion-induced apoptosis of coronary endothelial cells in vivo and consequently to improve endothelium-dependent relaxation of isolated coronary artery. Insulin treatment also attenuates apoptosis of cultured endothelial cells subjected to simulated ischemia and reperfusion by activation of PI3K/Akt and eNOS. The results of the study show that insulin shares the same signalling cascade for protection as previously described for myocardial tissue as a whole and for isolated cardiomyocytes, i.e. PI3K/Akt and eNOS [3]. These observations therefore indicate that this survival pathway is active also within the vascular compartment of the heart, rendering insulin even more important than before as a protective agent applicable to reperfused myocardial tissue. In apparent contrast to this optimistic view on insulin is the recent report of a large clinical trial. This study reported that high-dose GIK had only a “neutral” effect on mortality, cardiac arrest, and cardiogenic shock in patients with acute ST-segment elevation myocardial infarction (STEMI) [23]. The lack of effectiveness in this clinical study may have several causes. One complication was probably the frequency of hyperglycaemia, since achievement of normoglycaemia with intensive insulin therapy was shown to be indispensable to protect endothelium, preventing organ failure and death during critical illness [24]. Hyperglycaemia was shown to promote apoptotic cell death in myocardium in vivo through generation of reactive oxygen species; counteracting the beneficial effects of insulin [25]. The second shortcoming of this trial is the uncertainty about whether or not the critically narrow time frame for application of protective agents during the first few minutes of reperfusion was adequately respected. The identification of PI3K/Akt-eNOS as a survival pathway in endothelial cells is also important because eNOS can be activated by several agents such as HMG-CoA reductase inhibitors (statins) and G-protein-coupled receptor ligands such as adenosine receptor agonists or bradykinin [26,27].