Amplified Bioactive Signaling and Proteolytic Enzymes Following Ischemia Reperfusion and Aging
2010; Lippincott Williams & Wilkins; Volume: 122; Issue: 4 Linguagem: Inglês
10.1161/circulationaha.110.967414
ISSN1524-4539
Autores Tópico(s)Signaling Pathways in Disease
ResumoHomeCirculationVol. 122, No. 4Amplified Bioactive Signaling and Proteolytic Enzymes Following Ischemia Reperfusion and Aging Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAmplified Bioactive Signaling and Proteolytic Enzymes Following Ischemia Reperfusion and AgingRemodeling Pathways That Are Not Like a Fine Wine Francis G. Spinale, MD, PhD, FAHA Francis G. SpinaleFrancis G. Spinale From the Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC. Originally published12 Jul 2010https://doi.org/10.1161/CIRCULATIONAHA.110.967414Circulation. 2010;122:322–324Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 12, 2010: Previous Version 1 Left ventricular (LV) remodeling, defined as changes in myocardial structure and geometry, is considered to be a fundamental milestone in the progression to heart failure. This is particularly true in the clinical context of a myocardial infarction (MI), whereby adverse LV remodeling is directly associated with the progression to heart failure and increased morbidity and mortality.1 LV remodeling is a multifactorial process that includes changes within the myocardial, vascular and extracellular matrix (ECM). However, in terms of post-MI remodeling, changes in myocardial growth/viability and ECM structure/composition are ubiquitous events, and they occur in a heterogeneous fashion within the remote viable myocardium, the myocardial region surrounding the MI (border zone), and the MI scar itself. It is the summation of the alterations within both the cellular and extracellular compartments, which occur in all these regions post-MI, that promulgates adverse LV remodeling and ultimately the progression to heart failure. Through the use of animal models and clinical translational studies, certain signaling and proteolytic events have been identified to uniformly occur following an MI and to likely induce the cascade of events that yield changes in myocardial structure and function.2–8 In this issue of Circulation, Jugdutt and colleagues report on how the activation of a specific signaling pathway, the angiotensin-II receptor, influences a number of critical cellular signaling and ECM proteolytic events that can contribute to adverse LV remodeling.2 These investigators examined a number of critical pathways following a period of ischemia and reperfusion that resulted in a significant and relevant MI. These investigators not only examined these signaling/proteolytic events in a clinically-relevant model of MI, but, more importantly, they examined the post-MI remodeling process within the aging myocardium. The findings from this study are important for two reasons. Firstly, this study clearly demonstrated that important interactions occurred between the angiotensin-II receptor and the induction of bioactive molecules and proteases following an acute MI. Secondly, this study demonstrated that an amplified response occurs between these intersecting pathways within the aging myocardium following an acute MI. Taken together, the findings by Jugdutt and colleagues provide mechanistic evidence that the elderly myocardium is a more vulnerable substrate to an ischemic insult, and that this is likely due to enhanced/amplified induction of signaling cascades and proteolytic events that would directly contribute to a more advanced and accelerated LV remodeling process.Article see p 341Myocardial Cell Death Following MI and With AgingMyocyte loss following MI can occur through 3 different mechanisms: necrosis, apoptosis and defects in autophagy.6,9 While the first mechanism contributes to acute and significant loss of viable myocytes, it is likely that these other pathways contribute to continued myocyte cell death long after the acute event and can also contribute to progressive LV remodeling. Alterations in apoptosis and autophagy have been identified with aging,6,9 which would lead to the hypothesis that the aging myocardium, when subjected to a similar stress/insult, is more susceptible to adverse LV remodeling than the young myocardium. Indeed, an initial proteomic approach in aging mice identified alterations in levels of critical proteins involved in modulating oxidative stress.10 Jugdutt and colleagues identified that inducible nitric oxide synthase was robustly increased within the aging myocardium following an acute MI, which was paralleled by an induction of inflammatory mediators such as interleukin-6 and tumor necrosis factor.2 In these studies, infusion of an angiotensin-II receptor antagonist at the time of reperfusion significantly reduced these markers of oxidative stress and cytokine activation. Whether and to what degree the infusion of an angiotensin-II receptor antagonist at the time of the initial MI would prevent myocyte loss/remodeling through mediating apoptotic/autophagic pathways, and in turn cause a long-term favorable effect on LV remodeling, remains to be established. Nevertheless, this large animal model provides additional evidence that a "priming effect" exists within the senescent myocardium that would cause a robust increase in signaling pathways that contribute to adverse LV remodeling.Myocardial ECM Following MI and With AgingDegradation of the ECM following the acute phase of an MI is considered to be an essential event that allows for the ingress of inflammatory cells and the proliferation and maturation of macrophages and fibroblasts. It also provides the necessary substructure for scar formation. In the early part of the 20th century, it was identified that early (within 24 hours) after an MI, degradation of the normal collagen matrix occurred, which was then followed by significant matrix deposition.11 It is now recognized that the myocardial ECM is a complex microenvironment containing a large portfolio of matrix proteins, signaling molecules, proteases, and cell types that play a fundamental role in the post-MI remodeling process. In terms of the structure and composition of the ECM, a hallmark feature of the aging myocardium is increased collagen accumulation, which in turn impairs myocardial compliance and diastolic function. With respect to ECM signaling molecules, a pleiotropic bioactive molecule that plays a predominant role in the regulation of ECM synthesis is transforming growth factor (TGF). Alterations in the response of the aging myocardium to TGF, particularly following an MI, have been reported.4,8 The matricellular protein osteopontin is another bioactive molecule that can induce a potent profibrotic response both in vitro and in vivo.5 Both the TGF and osteopontin signaling pathways can be significantly influenced by angiotensin-II.4,5 The biosynthesis of ECM proteins, such as collagens, requires a series of post-translational steps, including appropriate localization, proteolytic processing, and ultimately, enzyme-mediated maturation and cross-linking. One of the matricellular proteins that has been recognized to play a role in post-translational processing of the ECM, and can contribute to adverse matrix remodeling with aging, is the secreted protein acidic and rich in cysteine.12 Secreted protein acidic and rich in cysteine facilitates the formation of mature collagen fibrils, and deletion of this matricellular protein can reduce collagen cross-linking and myocardial stiffness, particularly in aged mice.12 The study by Jugdutt and colleagues provides further demonstration of the interaction between the angiotensin-II receptor and the induction of profibrotic signaling molecules and matricellular proteins during the acute phase of MI.In addition to the stimulation of prosynthetic ECM pathways following an MI, the induction, activation and release of ECM proteolytic enzymes occur. These include serine proteases, matrix metalloproteinases (MMPs) and a-disintegrin and metalloproteinases. With respect to the MMPs, this constitutes a large family of proteolytic enzymes, and while the role of each of these MMPs is just beginning to be elucidated, a signature of certain MMP types appears to be released following an acute MI in patients. This includes the soluble MMP types MMP-2 and MMP-9.3,7 While the predominant pathway for MMP-2 activation is likely through another MMP type, the membrane type-1 MMP,3 an alternative activation mechanism that is likely to be operative in the context of acute tissue injury and inflammation, is through proteolytic processing by serine proteases. Inflammatory cells, such as macrophages and neutrophils, release certain MMP types, including MMP-9, serine proteases, and inhibitors of serine proteases, such as the secretory leukocyte protease inhibitor (SLPI).13 In past animal studies, it has been shown that SLPI can terminate the acute inflammatory mediated proteolytic response and facilitate wound healing.13 In the study by Jugdutt and colleagues, increased levels of proteolytic enzymes such as a-disintegrin and metalloproteinase-10, a-disintegrin and metalloproteinase-17, and MMP-2, as well as SLPI, were reported in the aging myocardium, and in turn would likely yield alterations in ECM homeostasis under steady state conditions as well as following acute MI.Aging, Myocardial Remodeling and Basic Research: A ParadoxCardiovascular disease, in particular, ischemic heart disease, is a function of age, where the incidence increases in almost an exponential fashion following the fifth decade of life.14 Clinically, it is well-recognized that elderly patients can be at much higher risk for LV remodeling and the progression to heart failure, despite an equivalent initial MI size when compared to younger cohorts of patients. The preponderance of basic research over the past decade, in terms of mechanisms and pathways that promulgate LV remodeling post-MI, have been performed in young mice using transgenic approaches. However, biological signaling pathways, proteolytic portfolios, and the overall response to myocardial injury can be quite different in these small, young rodents when compared to larger mammals.4,5,15 While these murine studies have provided invaluable insight and provoked new hypotheses, they must be carried forward through the use of large animals that more closely recapitulate the clinically-relevant context. Jugdutt and colleagues used a large animal model of aging and MI that demonstrated the complexity of the ECM with respect to being a reservoir for bioactive molecules, matrikines, and proteases, which are in a constant and dynamic balance (Figure); one that is likely to be much different within the aging myocardium. Unfortunately, the balance in these signaling/proteolytic pathways within the aging myocardium appears to be one that would favor a more aggressive and amplified adverse LV remodeling response following a myocardial insult. Download figureDownload PowerPointFigure. The myocardial ECM is a complex entity that forms a reservoir for bioactive signaling molecules (such as angiotensin-II, cytokines, TGF, and osteopontin (OPN)), matricellular proteins that regulate ECM structure (such as SPARC [secreted protein acidic and rich in cysteine]), proteases, and inhibitors (such as MMPs and SLPI). Under normal conditions, dynamic and likely continuous interactions between prototypical receptors such as the angiotensin-II receptor to profibrotic and matricellular proteins and the proteolytic enzymes determine the homeostatic balance of the ECM. The study in this issue of Circulation by Jugdutt and colleagues demonstrated that a shift in the balance if this system occurs within the aging myocardium, which would likely favor a more aggressive and amplified remodeling response following an acute MI. Following an acute MI, the release of cytokines such as interleukin-6 (IL-6) occurred, which was associated with an induction of TGF, OPN, and an array of proteolytic enzymes including MMPs (ie, MMP-2, MMP-9) as well as SLPI, many of which are likely released/induced by an acute inflammatory cell response. Jugdutt and colleagues demonstrated that this cytokine/matrikine/proteolytic cascade could be modified with an infusion of an angiotensin-II receptor antagonist.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.The author is grateful to Kaelyn Hawkins for creation of the figure.Sources of FundingThis work was supported by National Institutes of Health grants HL057952, HL059165, and by the Research Service of the Department of Veterans Affairs.DisclosuresNone.FootnotesCorrespondence to Francis G. Spinale, MD, PhD, Cardiothoracic Surgery, STRB Annex, 114 Doughty Street, Charleston, SC 29425. E-mail [email protected] References 1 St John Sutton M, Pfeffer MA, Moye L, Plappert T, Rouleau JL, Lamas G, Rouleau J, Parker JO, Arnold MO, Sussex B, Braunwald E. Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation. 1997; 96: 3294–3299.CrossrefMedlineGoogle Scholar2 Jugdutt BI, Jelani A, Palaniyappan A, Idikio H, Uweira RE, Menon V, Jugdutt CE. Aging-related early changes in markers of ventricular and matrix remodeling after reperfused ST-segment elevation myocardial infarction in the canine model: effect of early therapy with an angiotensin II type 1 receptor blocker. Circulation. 2010; 122: 341–351.LinkGoogle Scholar3 Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev. 2007; 87: 1285–1342.CrossrefMedlineGoogle Scholar4 Bujak M, Kweon HJ, Chatila K, Li N, Taffet G, Frangogiannis NG. Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction. J Am Coll Cardiol. 2008; 51: 1384–1392.CrossrefMedlineGoogle Scholar5 Singh M, Foster CR, Dalal S, Singh K. Role of osteopontin in heart failure associated with aging. Heart Fail Rev. 2010. Feb 3. [Epub ahead of print] PMID: 20127409. Accessed June 14, 2010.Google Scholar6 Cao DJ, Gillette TG, Hill JA. Cardiomyocyte autophagy: remodeling, repairing, and reconstructing the heart. Curr Hypertens Rep. 2009; 11: 406–411.CrossrefMedlineGoogle Scholar7 Webb CS, Bonnema DD, Ahmed SH, Leonardi AH, McClure CD, Clark LL, Stroud RE, Corn WC, Finklea L, Zile MR, Spinale FG. Specific temporal profile of matrix metalloproteinase release occurs in patients following myocardial infarction: relation to left ventricular remodeling. Circulation. 2006; 114: 1020–1027.LinkGoogle Scholar8 Dobaczewski M, Gonzalez-Quesada C, Frangogiannis NG. The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. J Mol Cell Cardiol. 2010; 48: 504–511.CrossrefMedlineGoogle Scholar9 Lee Y, Gustafsson AB. Role of apoptosis in cardiovascular disease. Apoptosis. 2009; 14: 536–548.CrossrefMedlineGoogle Scholar10 Dai Q, Escobar GP, Hakala KW, Lambert JM, Weintraub ST, Lindsey ML. The left ventricle proteome differentiates middle-aged and old left ventricles in mice. J Proteome Res. 2008; 7: 756–765.CrossrefMedlineGoogle Scholar11 Karsner HT, Dwyer JE. Studies in infarction: IV. Experimental bland infarction of the myocardium, myocardial regeneration and cicatrization. J Med Res. 1916; 34: 21–40. 3.MedlineGoogle Scholar12 Bradshaw AD, Baicu CF, Rentz TJ, Van Laer AO, Bonnema DD, Zile MR. Age-dependent alterations in fibrillar collagen content and myocardial diastolic function: role of SPARC in post-synthetic procollagen processing. Am J Physiol Heart Circ Physiol. 2010; 298: H614–H622.CrossrefMedlineGoogle Scholar13 Angelov N, Moutsopoulos N, Jeong MJ, Nares S, Ashcroft G, Wahl SM. Aberrant mucosal wound repair in the absence of secretory leukocyte protease inhibitor. Thromb Haemost. 2004; 92: 288–297.CrossrefMedlineGoogle Scholar14 Heart Disease and Stroke Statistics–2010 update. American Heart Association Web Site. http://www.americanheart.org/downloadable/heart/ 12626426574432010%20Stat%20charts%20FINAL.ppt. Published 2010. Accessed June 14, 2010.Google Scholar15 Lindsey ML, Goshorn DK, Squires CE, Escobar GP, Hendrick JW, Mingoia JT, Sweterlitsch SE, Spinale FG. Age-dependent changes in myocardial matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles and fibroblast function. Cardiovasc Res. 2005; 66: 410–419.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Malka A, Ertracht O, Bachner‐Hinenzon N, Reiter I and Binah O (2016) The cardioprotective efficacy of TVP 1022 against ischemia/reperfusion injury and cardiac remodeling in rats , Pharmacology Research & Perspectives, 10.1002/prp2.272, 4:6, Online publication date: 1-Dec-2016. Malka A, Meerkin D, Barac Y, Malits E, Bachner-Hinenzon N, Carasso S, Ertracht O, Angel I, Shofti R, Youdim M, Abassi Z and Binah O (2015) TVP1022, Journal of Cardiovascular Pharmacology, 10.1097/FJC.0000000000000267, 66:2, (214-222), Online publication date: 1-Aug-2015. Jugdutt B and Jelani A (2013) Aging and Markers of Adverse Remodeling After Myocardial Infarction Cardiac Remodeling, 10.1007/978-1-4614-5930-9_27, (487-512), . Singh R, Elimban V, Jassal D and Dhalla N (2013) Involvement of Proteolytic Enzymes in Cardiac Dysfunction Due to Ischemia-Reperfusion Injury Proteases in Health and Disease, 10.1007/978-1-4614-9233-7_22, (387-399), . Müller A, Hryshko L and Dhalla N (2013) Extracellular and intracellular proteases in cardiac dysfunction due to ischemia–reperfusion injury, International Journal of Cardiology, 10.1016/j.ijcard.2012.01.103, 164:1, (39-47), Online publication date: 1-Mar-2013. Singh R, Hryshko L, Freed D and Dhalla N (2012) Activation of proteolytic enzymes and depression of the sarcolemmal Na + /K + -ATPase in ischemia–reperfused heart may be mediated through oxidative stress , Canadian Journal of Physiology and Pharmacology, 10.1139/y11-128, 90:2, (249-260), Online publication date: 1-Feb-2012. July 27, 2010Vol 122, Issue 4 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.110.967414PMID: 20625106 Originally publishedJuly 12, 2010 KeywordsremodelingreperfusionEditorialsischemiamyocardial infarctionPDF download Advertisement SubjectsHeart Failure
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