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Cellular Biochemistry Laboratory Baker Heart Research Institute Melbourne 8008, Victoria, Australia
Address all correspondence and requests for reprints to: Elizabeth A. Woodcock, Cellular Biochemistry Laboratory, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne 8008, Victoria, Australia.
Acute ischemic episodes initiate cardiac arrhythmias and sudden death as well as loss of viable muscle cells that characteristically leads to progressive hypertrophy and subsequent heart failure. Although the incidence of sudden death following such heart attacks has decreased with increased availability and use of defibrillation, patients with sizable infarcts commonly progress to heart failure, with the result that heart failure is now a major cause of death in Western societies (1).
These two immediate responses, arrhythmias and infarction, are likely mediated via different signaling pathways and may also involve different receptor populations (2, 3, 4, 5). It is now known that ischemia/reperfusion causes substantial myocyte apoptosis acutely and by multiple mechanisms. The reduced blood supply in ischemia causes loss of oxidative phosphorylation and substrate supply, the net effect of which is hydrolysis of ATP and tissue acidification. The decreased intracellular pH is thought to be of critical significance for the apoptotic response (6). With short periods of ischemia, the acidity and related ionic imbalance can be reversed by reperfusion. However, surprisingly, inhibitors of these restorative processes, such as the Na+/H+ exchanger, are actually beneficial (7), possibly in part by reducing subsequent Ca2+ overload, which itself might stimulate apoptosis (8). In recent studies, ischemia/reperfusion has been shown to activate signal transducer and activator of transcription (STAT)-1 in heart and thereby to increase expression of Fas/Fas ligand and this likely also makes a major contribution to cell death via well characterized death receptor pathways (9, 10).
Studies of ischemia-induced apoptosis are always complicated by the concurrent activation of causative (proapoptotic) (9) and protective (antiapoptotic) pathways (11), and these can only really be distinguished by observing effects of inhibition or overstimulation of candidate intermediates. In addition, extensive cross-talk between the various signaling mechanisms further complicates interpretation (12). For example activation of STATs appears to be part of the apoptotic process, whereas ERK, Akt, and phosphatidylinositol 3-kinase (PI 3-kinase) are activated as part of the antiapoptotic program. c-Jun-NH2 terminal kinase (JNK) and p38 MAPKs might act either as facilitators or inhibitors of apoptosis in cardiomyocytes (13).
It is on this complex background that Brar et al. (14) have introduced a novel mechanism for protecting the myocardium during acute ischemic insults. They show that activation of corticotropin-releasing factor receptor 2 (CRFR2) that are expressed in the myocardium, reduces myocyte death in cellular models, and reduces infarct size in intact, perfused hearts. CRFR2 are receptors for corticotropin-releasing factor, a peptide expressed in the central nervous system, but not in peripheral tissues (15). In contrast, related peptides urocortin-1 (Unc-I), Unc-II, and Unc-III are expressed in the periphery, although exactly which isoforms are present seems to be species dependent. In mouse heart, Unc-I and Unc-II are expressed in addition to CRFR2. Thus, it is possible that cardiac CRFR2 orchestrate a paracrine program in cardiomyocytes. However, whereas expression of these peptides was demonstrated at the mRNA level, it is not known whether the active peptides are secreted constitutively, or in response to specific stimuli. In the current study, exogenous Unc-II and Unc-III were added to the cardiomyocytes or perfused heart, implying that, at least under these conditions of ischemia/reperfusion, sufficient peptide is not released to maximally activate CRFR2. This suggests that the CRFR2 system is not a major player in the heart’s endogenous mechanisms for limiting ischemic damage. However, this does not mean that CRFR2 are not a suitable target for intervention. The lack of saturation of this system, in fact, possibly makes it more attractive for therapeutic intervention.
A number of factors are known to reduce infarct size during acute iscaemia/reperfusion. The effectiveness of adenosine in this regard has been appreciated for many years (16), although in this case the protection is likely related to a combination of vasodilatation and preconditioning. More recently, protection from ischemic injury has been demonstrated using erythropoietin (17), statins (18, 19, 20), cardiotropin (21), and TGFß (22) among others. Statins appear to protect directly by effects on nitric oxide generation, independently of effects on cholesterol levels. In the current study, the authors suggest a role for ERK1/2 activation in cardioprotection by CRFR2. Many of the protective factors listed above are likely to activate ERK1/2, although possibly via different mechanisms. Ischemia/reperfusion activates ERK1/2 in cardiomyocytes as well as the stress-activated kinases JNK and p38 MAPKs (3). ERK1/2 undergoes phosphorylation with Unc-II and Unc-III stimulation in heart and thus could be involved in protection (11, 23), although this would require activation above that caused by ischemia/reperfusion alone. Activation of PI 3-kinase and related pathways also have been reported under ischemic conditions (11) and with Unc-II and Unc-III stimulation in cardiomyocytes (25). PI 3-kinase is a well-characterized antiapoptotic effector (26). PI 3-kinase was not specifically investigated in relation to Unc-II and Unc-III activity in the current study (14), although a role was reported in a previous paper (25).
Little is currently known about the functioning of CRFR2 in cardiomyocytes. Apparently myocardial CRFR2 are coupled to adenylyl cyclase and thus presumably to Gs. However, cAMP/protein kinase A does not appear to be instrumental in downstream ERK1/2 phosphorylation and antiapoptotic protection. The possibility that these receptors cross talk to growth factors receptors needs to be investigated, especially as they apparently can activate PI 3-kinase (25). The possibility of coupling to Gq is considered, but Gq activation is likely to be detrimental under these conditions (27, 28), although receptors that activate Gq can mimic ischemic preconditioning (29). Hearts from transgenic animals with cardiac targeted overexpression of constitutively active 
1B-adrenergic receptors that couple to Gq showed no protection and no worsening of infarct size or functional recovery after acute ischemic episodes (4). In contrast, hearts with overexpression of Gs-coupled ß2-adrenergic receptors were functionally protected (30).
Any loss of cells from the functioning myocardium represents a serious risk, as these cells are not traditionally thought to be regenerated, although this view is now being challenged (1). In chronic heart failure, loss of cells by apoptosis is minimal, although it may contribute to functional deterioration (31). A significant number of apoptotic cardiomyocytes have been reported only during acute ischemia/reperfusion (32, 33). Here the loss is transient and ceases several hours after the initial insult. This likely means that any antiapoptotic therapy might only be necessary immediately after the ischemic insult. This is important because chronic inhibition of apoptosis is likely to cause problems in tissues where unrestrained growth is undesirable.
Immediate loss of viable myocytes is likely to be a major determinant of subsequent cardiac hypertrophy and remodelling (34), and thus acute inhibition of apoptosis might provide long-term benefit. Demonstration of such long-term benefit is essential if CRFR2 ligands are to be considered for possible therapeutic applications, and more studies are required before any conclusions can be drawn about long-term effectiveness. Such studies could include survival after acute and chronic treatment with ligands such as Unc-II and Unc-III, and ideally these would be compared with other factors that similarly decrease infarct size. Functional studies showing improved contractile function will also strengthen the argument for further study of this receptor system in the heart.
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Received September 11, 2003.
Accepted for publication September 17, 2003.
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(1B)-adrenergic receptors in the heart does not alleviate ischemic reperfusion injury. J Mol Cell Cardiol 32:1679–1686[CrossRef][Medline]
(1B)-adrenergic receptors. Circ Res 83:1232–1240q activation of Akt-mediated cardiomyocyte survival pathways is compromised by PIP2 depletion. J Biol Chem 278:40343–40351 and PLC-ß in scar and border tissue in heart failure due to myocardial infarction. Circulation 97:892–899This article has been cited by other articles:
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  M. Huang, D. Kempuraj, N. Papadopoulou, T. Kourelis, J. Donelan, A. Manola, and T. C Theoharides Urocortin induces interleukin-6 release from rat cardiomyocytes through p38 MAP kinase, ERK and NF-{kappa}B activation J. Mol. Endocrinol., May 1, 2009; 42(5): 397 - 405. [Abstract] [Full Text] [PDF]
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