Inflammatory and apoptotic markers in ischemic heart disease patients

JMB 2008; 27 (2) DOI: 10.2478/v10011-008-0009-0 UDK 577.1 : 61 ISSN 1452-8258 JMB 27: 154 –160, 2008 INFLAMMATORY AND APOPTOTIC MARKERS IN ISCHEMIC HEART DISEASE PATIENTS MARKERI INFLAMACIJE I APOPTOZE KOD BOLESNIKA SA ISHEMIJSKOM BOLE[]U SRCA Vidosava B. \or|evi}1, Tatjana Risti}2, Vladan ]osi}2, Predrag Vlahovi}2, Lilika Zvezdanovi}2, Gordana \or|evi}3 1 Institute of Biochemistry, Faculty of Medicine, Ni{, Serbia Centre for Medical Biochemistry, Clinical Centre, Ni{, Serbia 3 Clinic for Neurology, Clinical Centre, Ni{, Serbia 2 Summary: Ischemic heart disease is the most frequent cause of cardiovascular morbidity and mortality. It is developed on the basis of atherosclerosis which is today considered a chronic inflammatory disease. It is documented by an increase in inflammatory and immune biomarkers, such as Creactive protein, fibrinogen, neopterin, leukocytes, lymphocytes and others, that are significantly changed in patients with unstable angina or acute myocardial infarction. CRP is mostly studied. Increased concentrations of CRP are associated with a series of risk factors. CRP may predict recurrent events and mortality independently of cardiac troponin levels, and it is also an independent predictor of a cardiovascular event after adjustment for traditional risk factors. Although CRP currently appears to be the most promising biological marker, there is still controversy regarding its use in clinical practice. Both necrotic and apoptotic cell death are documented during atherogenesis, however, limited data are available about apoptotic markers in ischemic heart disease patients. Increasing evidence supports the existence of apoptotic death initiated by ligation of membrane-bound death receptors or by release of cytochrome c from mitochondria, as well as their regulators in the heart. The studies of serum markers show that the apoptotic process is disregulated in ischemic heart disease patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is present in stable atherosclerotic lesions, is increased in vulnerable plaques, but its serum levels are reduced significantly in patients with unstable angina. Serum Fas concentrations are increased and FasL are decreased in subjects at high cardiovascular risk. The results of our study show significant changes in serum Fas, FasL, and Bcl-2 concentrations, and lymphocyte caspase-3 activity in different stages of ischemic heart disease. For now, there is evidence that statins are effective in the regulation of some apoptotic markers. The better understanding of the pathways of apoptosis and their regulation is promissing in yielding novel therapeutic targets for cardiovascular disease. Keywords: inflammatory markers, apoptotic markers, ischemic heart disease Address for correspondence: Vidosava B. \or|evi} Institute of Biochemistry, Faculty of Medicine, Ni{, Serbia Kratak sadr`aj: Ishemijska bolest srca je naj~e{}i uzrok kardiovaskularnog morbiditeta i mortaliteta. Razvija se na terenu ateroskleroze koja se danas smatra hroni~nom inflamatornom bole{}u. Inflamacija je dokazana pra}enjem inflamatornih i imunih biomarkera kao {to su C-reaktivni protein (CRP), fibrinogen, neopterin, leukociti, limfociti i drugi koji se zna~ajno menjaju kod bolesnika sa nestabilnom anginom pektoris ili akutnim infarktom miokarda. Naj~e{}e ispitivan marker je CRP. Pove}ane koncentracije CRP su udru`ene sa brojnim faktorima rizika. Na osnovu vrednosti CRP mogu se predvideti rekurentni doga|aji i mortalitet nezavisno od vrednosti sr~anog troponina, a tako|e je nezavisan prediktor kardiovaskularnog doga|aja nakon korekcije tradicionalnih faktora rizika. Iako se CRP trenutno smatra biolo{kim markerom koji najvi{e obe}ava, jo{ uvek postoje nedoumice u vezi sa njegovim kori{}enjem u klini~koj praksi. Mada je dokazano da se i nekroza i apoptoza de{avaju u toku aterogeneze, malo je dostupnih podataka koji se odnose na markere apoptoze kod bolesnika sa ishemijskom bole{}u srca. Sve je vi{e informacija koje ukazuju da se u srcu odvijaju apoptoza kao i njena regulacija, i da se apoptoza mo`e inicirati preko membranskih receptora smrti, ali i osloba|anjem citohroma c iz mitohondrija. Ispitivanje serumskih markera je pokazalo da je proces apoptoze poreme}en kod bolesnika sa ishemijskom bole{}u srca. TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) prisutan je u stabilnim aterosklerotskim lezijama, pove}an u vulnerabilnim plakovima, dok su njegove serumske vrednosti zna~ajno sni`ene kod bolesnika sa nestabilnom anginom. Koncentracija serumskog Fas je pove}ana, a FasL sni`ena kod osoba sa visokim rizikom. Rezultati na{e studije su pokazali zna~ajne promene koncentracija Fas, FasL i Bcl-2 u serumu, kao i aktivnost kaspaze-3 u limfocitima u razli~itim stadijumima ishemijske bolesti srca. Za sada postoje podaci o efektivnosti statina u regulaciji nekih markera apoptoze. Bolje razumevanje puteva apoptoze i njihove regulacije mo`e omogu}iti nov terapijski pristup kardiovaskularnim bolestima. Klju~ne re~i: markeri inflamacije, markeri apoptoze, ishemijska bolest srca JMB 2008; 27 (2) Introduction Despite the changes in lifestyle and the use of new pharmacological drugs to lower plasma lipid concentration (1, 2), cardiovascular diseases continue to be the principal cause of death in the United States, Europe, and much of Asia (3, 4). Among cardiovascular diseases, ischemic heart disease occurs most frequently. Atherosclerosis is validated in more than 90% of these patients. It is well known that inflammation plays a role in the initiation and the evolution of atherogenesis (5). Whatever the initial stimuli (mechanical, chemical, infectious or immunological), which depends on the nature of risk factors, a continuous ongoing inflammatory process leads to the evolution of an uncomplicated atheromatous plaque into complex and vulnerable atheroma. A flared plaque inflammation is considered a source of intimal erosion and rupture and therefore of acute ischemia (6). These studies are supported by the clinical findings of increased inflammatory markers in patients with chronic stable angina (7), unstable angina pectoris (8), and acute myocardial infarction (6). Furthermore, acute coronary syndrome is associated with both necrotic and apoptotic cell death. Necrosis is followed by a significant increase in troponines whilst apoptotic markers have not been well established yet. Also, there is evidence of the predictive value of inflammatory markers for subsequent coronary events (6). 155 Table I Biomarkers and mediators of inflammation and atherosclerosis. I Acute-phase reactants: – CRP (C-reactive protein) – Fibrinogen – SAA (Serum amyloid A) – Albumin – Leukocyte count II Indicators of activation of the immune system: – Lymphocytes – Neopterin – Immunoglobulins (IgA, IgE, IgG, IgM) – Serum complement (Total, C3) – Circulating immune complexes – Circulating antitissue antibodies III Cytokines: – IFN-g – MCP-1 (monocyte chemot (...truncated)