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• W1600852032 abstract "The old axiom ‘one protein, one function’ no longer holds true. Activated protein C (APC), the serine protease which plays a central role in anticoagulation, has gained attention because of its unsuspected (until a decade ago) ability to promote cell signaling mechanisms leading to cell/tissue protection. Since the PROWESS clinical trial initially pointed at APC as the only drug able to reduce the mortality associated with severe sepsis [1Bernard G.R. Vincent J.L. Laterre P.F. LaRosa S.P. Dhainaut J.F. Lopez‐Rodriguez A. Steingrub J.S. Garber G.E. Helterbrand J.D. Ely E.W. Fisher Jr, C.J. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study groupEfficacy and safety of recombinant human activated protein C for severe sepsis.N Engl J Med. 2001; 344: 699-709Crossref PubMed Scopus (5083) Google Scholar], many studies in animal models have demonstrated that APC shows promise in a variety of pathologies. Diabetic nephropathy, inflammatory bowel disease, systemic lupus erythematosus, amyotrophic lateral sclerosis (ALS), cancer metastasis and ischemic stroke are among the conditions that APC could help to fight against, thanks to its anti‐adhesive, anti‐apoptotic or barrier enhancement abilities [2Montes R. Puy C. Molina E. Hermida J. Is EPCR a multi‐ligand receptor? Pros and cons.Thromb Haemost. 2012; 107: 815-26Crossref PubMed Scopus (24) Google Scholar]. The appealing findings presented in this issue of the Journal of Thrombosis and Haemostasis by Costa et al. [3Costa R. Morrison A. Wang J. Manithody C. Li J. Rezaie A.R. Activated protein C modulates cardiac metabolism and augments autophagy in the ischemic heart.J Thromb Haemost. 2012; 10: 1736-44Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar] not only illustrate the pleiotropic nature of APC actions, they may also constitute an original approach to a widely prevalent pathological condition, i.e. the ischemia‐reperfusion (I/R) related myocardial injury subsequent to coronary reperfusion, for which no specific treatments have been developed. The authors recently described in a murine I/R model how APC attenuated the acute myocardial ischemic injury by stimulating the AMP‐activated protein kinase (AMPK) signaling pathway [4Wang J. Yang L. Rezaie A.R. Li J. Activated protein C protects against myocardial ischemic/reperfusion injury through AMP‐activated protein kinase signaling.J Thromb Haemost. 2011; 9: 1308-17Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. APC exerted this effect by acting via its canonical receptors, the endothelial cell protein C/APC receptor (EPCR) and the protease activated receptor‐1 (PAR‐1), which orchestrate a cascade of reactions dictated by G‐proteins which finally result in cytoprotective effects. This study did not go beyond the APC‐dependent modulation of such pathway. However, the authors did not ignore the fact that the AMPK signaling pathway has been implicated in the protection of the myocardium against I/R injury because of its ability to regulate the cardiac metabolism in response to ischemic stress [5Russell 3rd, R.R. Li J. Coven D.L. Pypaert M. Zechner C. Palmeri M. Giordano F.J. Mu J. Birnbaum M.J. Young L.H. AMP‐activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury.J Clin Invest. 2004; 114: 495-503Crossref PubMed Scopus (628) Google Scholar, 6Young L.H. AMP‐activated protein kinase conducts the ischemic stress response orchestra.Circulation. 2008; 117: 832-40Crossref PubMed Scopus (73) Google Scholar]. For this reason, they have now proposed the attractive hypothesis that APC could help to balance the energy demand and supply in response to ischemic stress. In other words, optimize the metabolic performance of the little oxygen available in such a condition. Using an elegant ex vivo model, they have discovered that APC, when administered before reperfusion, is able: first, to promote the oxidation of glucose over fatty acids as the preferred energy substrate by inducing the translocation of the glucose transporter GLUT4 to the cardiomyocyte cell membrane; and second, to further improve the glucose homeostasis by increasing the I/R‐triggered autophagy, the self‐eating cell process that has been related to modulation of glucose homeostasis under stress conditions. The findings described herein by Costa et al. must be put together with their previous observations that APC succeeded in reducing the myocardial infarct size subsequent to I/R in mice [4Wang J. Yang L. Rezaie A.R. Li J. Activated protein C protects against myocardial ischemic/reperfusion injury through AMP‐activated protein kinase signaling.J Thromb Haemost. 2011; 9: 1308-17Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. Thus, an APC‐based treatment strategy may be considered for this highly prevalent condition. Nevertheless, a few concerns should be approached beforehand: although the AMPK‐related pathways constitute an important regulatory mechanism in the heart, and animal models of ischemia and I/R have reported beneficial effects of metformin, an AMPK activator, by decreasing infarct size and blunting heart failure [7Yin M. van der Horst I.C. van Melle J.P. Qian C. van Gilst W.H. Sillje H.H. de Boer R.A. Metformin improves cardiac function in a nondiabetic rat model of post‐MI heart failure.Am J Physiol. 2011; 301: H459-68Crossref PubMed Scopus (135) Google Scholar], there is no general consensus that the shift in substrate oxidation from fatty acids towards carbohydrates is necessarily beneficial for the myocardium. Indeed, the oxidation of glucose is more efficient than that of fatty acids in terms of oxygen cost i.e. more energy is obtained. However, in absolute terms, the oxidation of one molecule of fatty acid yields far more ATP than glucose [8van Bielsen M. van Nieuwenhoven F.A. van der Vusse G.J. Metabolic remodelling in the failing heart: beneficial or detrimental.Cardiovasc Res. 2009; 81: 420-8Crossref PubMed Scopus (140) Google Scholar]. Furthermore, a sustained decline in fatty acid oxidation may result in an excessive accumulation of lipids which could lead to contractile dysfunction and, eventually, cell death [9Wende A.R. Abel E.D. Lipotoxicity in the heart.Biochim Biophys Acta. 2010; 1801: 311-9Crossref PubMed Scopus (250) Google Scholar]. On the other hand, the exact role autophagy has in ischemia and I/R is also controversial. Interruption of blood flow to the myocardium disrupts oxygen supply, triggering rapid declines in ATP and increased AMP/ATP ratios. Autophagy, as a pro‐survival mechanism that replenishes energy under stress conditions, is activated. Ischemia/hypoxia induces autophagy in vivo and in vitro in most [10Matsui Y. Takagi H. Qu X. Abdellatif M. Sakoda H. Asano T. Levine B. Sadoshima J. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP‐activated protein kinase and Beclin 1 in mediating autophagy.Circ Res. 2007; 100: 914-22Crossref PubMed Scopus (1261) Google Scholar, 11Yan L. Vatner D.E. Kim S.J. Ge H. Masurekar M. Massover W.H. Yang G. Matsui Y. Sadoshima J. Vatner S.F. Autophagy in chronically ischemic myocardium.Proc Natl Acad Sci USA. 2005; 102: 13807-12Crossref PubMed Scopus (456) Google Scholar], although not all [12French C.J. Taatjes D.J. Sobel B.E. Autophagy in myocardium of murine hearts subjected to ischemia followed by reperfusion.Histochem Cell Biol. 2010; 134: 519-26Crossref PubMed Scopus (20) Google Scholar], studies. If ischemia is prolonged, the autophagic response becomes dysfunctional, as evidenced by the existence of impaired autolysosomes. Additionally, during reperfusion, autophagy is upregulated further, even although the delivery of oxygen and nutrients is restored and AMPK is rapidly inactivated [10Matsui Y. Takagi H. Qu X. Abdellatif M. Sakoda H. Asano T. Levine B. Sadoshima J. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP‐activated protein kinase and Beclin 1 in mediating autophagy.Circ Res. 2007; 100: 914-22Crossref PubMed Scopus (1261) Google Scholar, 13Hamacher‐Brady A. Brady N.R. Gottlieb R.A. Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes.J Biol Chem. 2006; 281: 29776-87Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar]. The continued activation of autophagy during reperfusion is qualitatively different than that in ischemia, especially in terms of mechanisms of induction. Stimulators, such as oxidative stress, mitochondrial damage/BNIP3, endoplasmic reticulum stress and calcium overload, probably have more important roles in maintaining autophagy at a higher level during reperfusion [14Gustafsson A.B. Gottlieb R.A. Autophagy in ischemic heart disease.Circ Res. 2009; 104: 150-8Crossref PubMed Scopus (315) Google Scholar]. Although the available evidence is consistent that autophagy is protective under conditions of mild‐to‐moderate ischemia, the same cannot be said of autophagy elicited by reperfusion. Indeed, upregulation of autophagy can be either beneficial or detrimental in the context of I/R [10Matsui Y. Takagi H. Qu X. Abdellatif M. Sakoda H. Asano T. Levine B. Sadoshima J. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP‐activated protein kinase and Beclin 1 in mediating autophagy.Circ Res. 2007; 100: 914-22Crossref PubMed Scopus (1261) Google Scholar, 13Hamacher‐Brady A. Brady N.R. Gottlieb R.A. Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes.J Biol Chem. 2006; 281: 29776-87Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar]. Although animal models suggest the usefulness of APC in diverse inflammatory settings, severe sepsis is the only clinical condition in which APC has been used. As mentioned above, the PROWESS clinical trial initially showed that treatment with APC in patients with severe sepsis was associated with a reduction in the absolute risk of death compared with standard measures [1Bernard G.R. Vincent J.L. Laterre P.F. LaRosa S.P. Dhainaut J.F. Lopez‐Rodriguez A. Steingrub J.S. Garber G.E. Helterbrand J.D. Ely E.W. Fisher Jr, C.J. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study groupEfficacy and safety of recombinant human activated protein C for severe sepsis.N Engl J Med. 2001; 344: 699-709Crossref PubMed Scopus (5083) Google Scholar]. Very recently, this topic has been revisited by the PROWESS‐SHOCK study, which, managing a number of patients similar to that used in the initial study (∼1700), was unable to replicate the results of PROWESS. PROWESS‐SHOCK concluded that APC did not significantly reduce mortality, as compared with placebo, in patients with septic shock [15Ranieri V.M. Thompson B.T. Barie P.S. Dhainaut J.F. Douglas I.S. Finfer S. Gårdlund B. Marshall J.C. Rhodes A. Artigas A. Payen D. Tenhunen J. Al‐Khalidi H.R. Thompson V. Janes J. Macias W.L. Vangerow B. Williams MD; PROWESS‐SHOCK Study GroupDrotrecogin alfa (activated) in adults with septic shock.N Engl J Med. 2012; 366: 2055-64Crossref PubMed Scopus (963) Google Scholar]. As a consequence, the Food and Drug Administration has recommended that APC treatment should not be started in new patients. Should this discourage scientists from considering APC a promising drug in this, or other clinical settings? We do not think so. First, patients eligible in the PROWESS and PROWESS‐SHOCK trials presented with several dysfunctional organs or systems, systemic inflammation and shock, and were receiving fluids and vasopressors at the time of enrollment [1Bernard G.R. Vincent J.L. Laterre P.F. LaRosa S.P. Dhainaut J.F. Lopez‐Rodriguez A. Steingrub J.S. Garber G.E. Helterbrand J.D. Ely E.W. Fisher Jr, C.J. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study groupEfficacy and safety of recombinant human activated protein C for severe sepsis.N Engl J Med. 2001; 344: 699-709Crossref PubMed Scopus (5083) Google Scholar, 15Ranieri V.M. Thompson B.T. Barie P.S. Dhainaut J.F. Douglas I.S. Finfer S. Gårdlund B. Marshall J.C. Rhodes A. Artigas A. Payen D. Tenhunen J. Al‐Khalidi H.R. Thompson V. Janes J. Macias W.L. Vangerow B. Williams MD; PROWESS‐SHOCK Study GroupDrotrecogin alfa (activated) in adults with septic shock.N Engl J Med. 2012; 366: 2055-64Crossref PubMed Scopus (963) Google Scholar]. In other words, they were in such a severe condition that success in treatment was extremely difficult. Second, as APC possesses a potent anticoagulant activity, it had to be cautiously administered to avoid bleeding, thus possibly missing additional beneficial effects which higher doses would have produced. Third, APC triggers the major part of its non‐coagulation related effects through the EPCR‐PAR‐1 axis. EPCR has been recently described to be under the control of secretory group V phospholipase A2 (sPLA2‐V), which promotes the substitution of the phosphatidylcholine molecule that stabilizes the EPCR structure by lysophosphatidylcholine or platelet activating factor. As a result, this ‘encrypted’ EPCR is no longer able to bind to protein C/APC properly [16López‐Sagaseta J. Puy C. Tamayo I. Allende M. Cerveró J. Velasco S.E. Esmon C.T. Montes R. Hermida J. sPLA2‐V inhibits EPCR anticoagulant and antiapoptotic properties by accommodating lysophosphatidylcholine or PAF in the hydrophobic groove.Blood. 2012; 119: 2914-21Crossref PubMed Scopus (20) Google Scholar]. sPLA2‐V is increased in conditions such as infection or atherosclerosis [17Dudek S.M. Muñoz N.M. Desai A. Osan C.M. Meliton A.Y. Leff A.R. Group V phospholipase A2 mediates barrier disruption of human pulmonary endothelial cells caused by LPS in vitro.Am J Respir Cell Mol Biol. 2011; 44: 361-8Crossref PubMed Scopus (21) Google Scholar, 18Rosengren B. Peilot H. Umaerus M. Jönsson‐Rylander A.C. Mattsson‐Hultén L. Hallberg C. Cronet P. Rodriguez‐Lee M. Hurt‐Camejo E. Secretory phospholipase A2 group V: lesion distribution, activation by arterial proteoglycans, and induction in aorta by a Western diet.Arterioscler Thromb Vasc Biol. 2006; 26: 1579-85Crossref PubMed Scopus (78) Google Scholar]. It is at least conceivable that septic patients may not have made the most of APC therapy as a result of the inability of EPCR to trigger protective signals. This point should at least be considered to ensure the success of APC in future trials. Although APC can be considered as a potentially useful clinical tool, its ugly side still remains (i.e. the bleeding risk associated with its anticoagulant activity). This may be particularly important for patients with cardiac I/R or ischemic stroke, who would be under concomitant antiplatelet, anticoagulant or fibrinolytic therapy. However, this limitation is about to be overcome. Site‐directed mutagenesis has made it possible to engineer protein C variants that are devoid of anticoagulant activity while preserving cell signaling properties. These molecules have been successfully tested in endotoxemia, ALS and ischemic stroke models [19Kerschen E.J. Fernandez J.A. Cooley B.C. Yang X.V. Sood R. Mosnier L.O. Castellino F.J. Mackman N. Griffin J.H. Weiler H. Endotoxemia and sepsis mortality reduction by non‐anticoagulant activated protein C.J Exp Med. 2007; 204: 2439-48Crossref PubMed Scopus (258) Google Scholar, 20Zhong Z. Ilieva H. Hallagan L. Bell R. Singh I. Paquette N. Thiyagarajan M. Deane R. Fernandez J.A. Lane S. Zlokovic A.B. Liu T. Griffin J.H. Chow N. Castellino F.J. Stojanovic K. Cleveland D.W. Zlokovic B.V. Activated protein C therapy slows ALS‐like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells.J Clin Invest. 2009; 119: 3437-49PubMed Google Scholar, 21Guo H. Singh I. Wang Y. Deane R. Barrett T. Fernández J.A. Chow N. Griffin J.H. Zlokovic B.V. Neuroprotective activities of activated protein C mutant with reduced anticoagulant activity.Eur J Neurosci. 2009; 29: 1119-30Crossref PubMed Scopus (70) Google Scholar] and one of them has even been successfully assessed for preclinical safety to support initiation of ischemic stroke clinical trials [22Williams P.D. Zlokovic B.V. Griffin J.H. Pryor K.E. Davis T.P. Preclinical safety and pharmacokinetic profile of 3K3A‐APC, a novel, modified activated protein C for ischemic stroke.Curr Pharm Des. 2012; 18: 4215-22Crossref PubMed Scopus (43) Google Scholar]. The work presented by Costa et al. in this issue makes a significant contribution to this field as well [3Costa R. Morrison A. Wang J. Manithody C. Li J. Rezaie A.R. Activated protein C modulates cardiac metabolism and augments autophagy in the ischemic heart.J Thromb Haemost. 2012; 10: 1736-44Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]. The authors engineered a disulfide bond between two beta‐sheets of protein C to prevent Ca2 + binding to one loop of the molecule. As a result, once activated, its anticoagulant activity was dramatically reduced while its EPCR‐PAR‐1‐dependent cell signaling ability was minimally altered [23Bae J.S. Yang L. Manithody C. Rezaie A.R. Engineering a disulfide bond to stabilize the calcium‐binding loop of activated protein C eliminates its anticoagulant but not its protective signaling properties.J Biol Chem. 2007; 282: 9251-9Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. This so‐called APC‐2Cys was notably more efficient than APC in promoting glucose oxidation, preventing fatty acid oxidation and improving the redox status in the heart upon I/R‐induced cardiac injury [3Costa R. Morrison A. Wang J. Manithody C. Li J. Rezaie A.R. Activated protein C modulates cardiac metabolism and augments autophagy in the ischemic heart.J Thromb Haemost. 2012; 10: 1736-44Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]. Thus this APC variant could be particularly useful, as the sudden increase in the oxygen level after reperfusion leads to enhanced fatty acid oxidation and subsequent generation of reactive oxygen species to cause cardiac damage. Why is APC‐2Cys superior to APC in promoting these actions? This finding was not expected as the authors had previously reported that the affinity of APC‐2Cys for EPCR was slightly lower than the affinity of the wild‐type counterpart [23Bae J.S. Yang L. Manithody C. Rezaie A.R. Engineering a disulfide bond to stabilize the calcium‐binding loop of activated protein C eliminates its anticoagulant but not its protective signaling properties.J Biol Chem. 2007; 282: 9251-9Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. APC is sometimes able to trigger cell signaling pathways in an EPCR‐independent manner, in processes involving protease‐activated receptors or the apolipoprotein E receptor 2 [24Guo H. Liu D. Gelbard H. Cheng T. Insalaco R. Fernández J.A. Griffin J.H. Zlokovic B.V. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3.Neuron. 2004; 41: 563-72Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 25O’Brien L.A. Richardson M.A. Mehrbod S.F. Berg D.T. Gerlitz B. Gupta A. Grinnell B.W. Activated protein C decreases tumor necrosis factor related apoptosis‐inducing ligand by an EPCR‐ independent mechanism involving Egr‐1/Erk‐1/2 activation.Arterioscler Thromb Vasc Biol. 2007; 27: 2634-41Crossref PubMed Scopus (52) Google Scholar, 26Yang X.V. Banerjee Y. Fernández J.A. Deguchi H. Xu X. Mosnier L.O. Urbanus R.T. de Groot P.G. White‐Adams T.C. McCarty O.J. Griffin J.H. Activated protein C ligation of ApoER2 (LRP8) causes Dab1‐dependent signaling in U937 cells.Proc Natl Acad Sci USA. 2009; 106: 274-9Crossref PubMed Scopus (96) Google Scholar, 27Madhusudhan T. Wang H. Straub B.K. Gröne E. Zhou Q. Shahzad K. Müller‐Krebs S. Schwenger V. Gerlitz B. Grinnell B.W. Griffin J.H. Reiser J. Gröne H.J. Esmon C.T. Nawroth P.P. Isermann B. Cytoprotective signaling by activated protein C requires protease‐activated receptor‐3 in podocytes.Blood. 2012; 119: 874-83Crossref PubMed Scopus (92) Google Scholar]. Could APC‐2Cys present a higher affinity for one of these receptors and this be involved in mediating some of the effects on the cardiomyocyte metabolism? This question will foster further research. In any case, the good news is that the work of Costa et al. contributes to the growing body of research that suggests the disappointment caused by the PROWESS‐SHOCK trial may turn into hope thanks to the engineered variants of APC. The authors state that they have no conflict of interest. Financial support was provided by the Unión Temporal de Empresas project CIMA, Instituto de Salud Carlos III (PI08/1349, PI10/01432 and Red Temática de Investigación RECAVA RD06/0014/0008) and the Health Department, Gobierno de Navarra (15/09)." @default.
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• W1600852032 title "Activated protein C: reasons to believe" @default.
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