| المجلد 3 , العدد 8 , جمادى الآخرة 1426 - تموز (يوليو) 2005 |
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بروتينات المطرس الخلوي والبروتينات الرابطة للكالسيوم:
واصمات بيولوجية جديدة لفشل القلب والأمراض القلبية الوعائية
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| Matricellular Proteins and Calcium Binding Proteins: New Biomarkers of Heart Failure and Cardiovascular Diseases? |
| Gruson Damien
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| Laboratory of Clinical Endocrinology, Cliniques Universitaires St-Luc, Bruxelles, Belgium. |
| الملخص Abstract |
يعد فشل القلب Heart Failure مرضاً مدمراً، ويزداد معدل انتشاره في مرحلة الكهولة، ويموت نصف المصابين به خلال السنوات الخمس من تشخيصه.
لفشل القلب فيزيولوجيا مرضية معقدة، وله أعراض مختلفة وغالباً نوعية، ولقد اشتد الاهتمام بتطوير واصمات بيولوجية – هي موضوع البحث في هذه المقالة القصيرة – لتبئ عن الإنذار وتساعد في وضع التشخيص المبكر وتدبير المريض.
تتجلى المميزات الكبرى لفشل القلب بحدوث شذوذات في كل من وظيفة البطين الأيسر، والتنظيم الهرموني العصبي.
ولوضع التشخيص البدئي والتشخيص التفريقي، أوصت الجمعية الدولية لأمراض القلب وبشكل متواتر، ببتيدات مدرة للصوديوم Natriuretic Peptides تتدخل في آليات التنظيم الهرموني العصبي، وعدت ذلك إجراءاً مطلوباً. يشكل كل من: الببتيد الشرياني الأذيني المدر للصوديوم ANP، والببتيد المدر للصوديوم من النمط B (BNP) وشدف المطراف الأميني لهما، الواصمات البيولوجية الأكثر شيوعاً لتشخيص فشل القلب ووضع الإنذار. أما الببتيدات الأخرى، مثل: Adrenomedullin، Endothelin، Vasopressin، Apelin و Adiponectin، فلقد تم اعتبارها كوسائل مساعدة في تشخيص فشل القلب ووضع إنذاره.
السمات المرضية الأخرى التي تدمغ داء "فشل القلب" هي: إعادة الصوغ المرضية لنسيج القلب والتي تؤدي إلى تبدلات بنيوية ووظيفية مؤذية للخلية العضلية وعلى مستويات العضل القلبي وحجيراته (أجوافه).
عُرف من التبدلات الطارئة على القلب تلك التي تخص المطرس خارج الخلوي Exrtacellulary matrix وأضيف لها مؤخراً: بروتينات المطرس الخلوي MP والبروتين الرابط للكالسيوم CBP مثل: البروتين S100 B، وهي بروتينات تشارك في إعادة الصوغ القلبي وفشل القلب.
علاوة على ذلك: تم كشف وجود بروتينات المطرس السابقة في مواقع التكلس وتشكل العظم الغضروفي، في الجملة الوعائيـة التاجيـة (الإكليليـة)، وهذا ما طرح آلية محتملة
لحدوث التكلس التاجي (الإكليلي).
في هذه المقالة الصغيرة: توكيد لأهمية هذه الواصمات البيولوجية المحتملة، ودورها في الأمراض القلبية الوعائية.
المناقشة ووجهات النظر (التطلعات):
تدل البنية الظاهرة للعيان على أن بروتينات المطرس MPs و CBP ليست فقط عامل تحصين لمنظمات الكالسيوم أو العظم، بل هي في الواقع يمكن أن تفعل كعوامل محصّنة للجملة الوعائية، وتلعب دوراً حاسماً في إعادة الصوغ القلبي للقلب المجهد، فهي تؤكد المشاركة بين وسطاء استتباب العظم ومرض القلب الوعائي، وبالتالي فهي تعطي دليلاً على أن MP و CBP يمكن أن يُعدا واصمان جديدان للحوادث القلبية الوعائية، وإعادة صوغ القلب، والتكلس الوعائي، وهي أيضاً مُنبِّئات للموت بعد الحوادث القلبية. |
| Introduction |
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Heart Failure (HF) is a devastating disease with increasing prevalence in elderly populations. One half of all patients die within the 5 years of diagnostic. HF had a complex pathophysiology, varied and often aspecific symptoms and interest has intensified in developing biological markers to predict the prognosis and aid the early diagnosis and management of this disease. Abnormalities in left ventricular function and neurohormonal regulation are major characteristics of this condition (1). To make initial and differential diagnosis, natriuretic peptides involved in the neurohormonal regulation are frequently used and recommended to this end by international societies of cardiology. Atrial Natriuretic Peptide (ANP), B-type Natriuretic Peptide (BNP) and their N-terminal fragments are actually the most popular biomarkers for HF diagnosis and prognosis. Other peptides like Adrenomedullin, Endothelin, Vasopressin, Apelin or Adiponectin could be consider as interesting tools to improve HF diagnosis and prognosis (2-4).
Another pathological hallmark of HF is pathologic remodelling of the cardiac tissue that lead to deleterious, functional and structural changes at the myocyte, myocardial and chamber levels. These changes involved extracellular matrix and recently, Matricellular Proteins (MP) and Calcium Binding Protein (CBP) like S100B protein were associated with cardiac remodelling and HF. Moreover, MP has been identified at sites of calcifications (5) and endochondral bone formation in the coronary vasculature, suggesting as a possible mechanism of coronary calcifications (6).
In this short review, emphasis will be placed on the description of these potential new biomarkers and their roles in cardiovascular diseases. |
| Overview of Osteopontin, Osteo-protegerin, Osteonectin and S100B |
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Osteopontin, Osteoprotegerin and Osteonectin are members of the MP family and protein S100B is a specific calcium binding protein. MP are matrix proteins that modulate cell function but do not appear to have a direct structural role in the extracellular matrix of the heart. MP common property is their high expression during embryogenesis, which strongly decreases after birth, when expression becomes low to absent during normal adult life (7). Their expression re-appears at high levels during remodelling, wound healing and tissue injury. S100 is a multigenic family of calcium binding proteins of the EF-hand type, implicated in intracellular and extracellular modulatory activities.
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Osteopontin (OPN) is an adhesion molecule which was first identified in bone by Reinholt et al. (8). OPN is a large acid phosphoprotein adhesion molecule that is secreted by both cardiac interstitial fibroblasts and myocytes (9; 10). OPN contains the Arginin-Glycin-Aspartate tripeptide integrin binding motif and, by acting as an integrin ligand, OPN can activate cell signalling pathways and gene expression and thereby regulate cell differentiation and function (11). OPN appears as a multifunctional protein, not only expressed by bone cells, but also by inflammatory and wound healing cells, including macrophages, endothelial cells, smooth muscle cells and fibroblasts (12). OPN has both pro- and anti-inflammatory effects by regulating inflammatory cell adhesion (13), migration (14), cytokine release and differenciation state (15).
Osteoprotegerin (OPG) is a MP member of the tumor necrosis factor (TNF) receptor superfamily that can function as a soluble decoy receptor by binding receptor activator of nuclear factor K B ligand (RANKL), thus competitively inhibiting interaction between RANKL and its receptor (16). OPG is involved in paracrine signalling in bone metabolism and in immune responses by modulating T-cell function and antibody response.
Osteonectin (OTN), another MP, is implicated in remodelling through binding to thrombospondin 1, vitronectin, entactin, fibrillar collagens and collagen type IV and in the regulation of extracellular matrix organization (17). OTN also mediated cell-extracellular matrix interactions (18).
One of the 19 members of S100 family is the S100B protein. S100B is a 20kD EF-hand calcium binding dimer which is physiologically, produces and released primarly by astrocytes in the central nervous system, where it exerts neurotrophic and gliotrophic actions. Measurement of S100B level in blood is a potential tool to evaluate neural injury, blood-brain barrier dysfunction or stroke (19). S100B has been implicated in the regulation of a number of intracellular activities by its interaction with effectors proteins.
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MP and CBP: potential biomarkers of heart failure and remodelling
OPN, OPG and OTN appear as markers of HF and cardiac remodelling.
OPN mRNA is up-regulated in left ventricular hypertrophy and failure in humans and animal models (20). In 2002, Stawowy et al., shown that factors and/or mechanisms involved in heart failure in patients with dilated cardiomyopathy, lead to induction of OPN expression in human (21). Collins et al. found that OPN mediates cardiac fibrosis, probably through the modulation of cellular adhesion and proliferation (22). Moreover, lack of OPN in OPN null mice attenuates fibrosis. Ashizawa et al. found that OPN expression in the heart is potently regulated by angiotensin II and OPN is an important factor controlling cardiac fibroblast growth, adhesion to extracellular matrix and collagen contraction (23). Finally, Ketelslegers et al., shown that a high degree of neurohormonal pro-inflammatory cytokines and collagen remodelling activation, including OPN, may be indicative of a poor prognosis for patients with post AMI HF despite subsequent optimal therapy.
OPG mRNA and protein expression have been detected in myocardial tissue and atherosclerotic plaque (24). OPG levels have been associated with the presence and severity of coronary artery disease. Kiechl et al., demonstrated that OPG level is a risk factor of cardiovascular disease in the general population (25). Ueland et al., demonstrated that OPG is a novel marker for cardiovascular mortality and clinical events in patients with AMI complicated with HF especially in the fourth quartile of OPG concentration (26).
OTN expression re-appears in the heart after myocardial infarction (27) or adrenergic stimulation(28). After MI, OTN mRNA expression reach a peak after 14 days and its expression paralleled the up-regulation of type I collagen mRNA, suggesting an implication in remodelling and fibrosis. OTN may also modulate de-adhesion and facilitate myocyte slippage and cardiac dilatation and angiogenesis and might influence infarct healing after MI (29).
Tsoporis et al have identified S100B as a putative intrinsic negative-feedback regulator of the hypertrophic response induced in the myocardium after MI in human subjects and have shown it to be capable of inhibiting the a-1-adrenergic-induced hypertrophy in cultured neonatal rat cardiac myocytes (30).
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MP and CBP in vascular calcification regulation
Calcium deposition is associated with the atherosclerotic process and with the high likelihood of adverse events such as myocardial infarction and coronary death. With the greater longevity enjoyed by many individuals today, the deleterious clinical consequences of vascular calcification are now evident: stroke, amputation and cardiovascular mortality are portended by the anatomy and extent of calcific vasculopathy. Moreover, metabolic stimuli contribute to calcific vascular disease initiation and progression, and for example, patients with diabetes have increased mortality and risk for lower-extremity amputation in the setting of medial artery calcification (31). Vascular calcium deposition can be usefully organized into four histoanatomic variants: atherosclerotic/fibrotic calcification, cardiac valve calcification, medial artery calcification and vascular calciphylaxis.(32). In the past, coronary calcification was perceived as a passive precipitation of mineral. More recently, evidence suggests that arterial calcification is the result of an organized, regulated process with similarities to osteogenesis (33). Now, there is evidence of involvement of MP with calcium affinity and CBP in the process of vascular calcifications.
The effects of OPN in vascular disease are complex. Regulation of matrix metalloproteinases is central to OPN actions in the vascular remodelling that controls medial thickening (34). OPN deficiency in animal model results in excessive calcium deposition (35) and OPN seems to serve to inhibit calcification of vascular structures in vivo. Phosphorylated OPN inhibits bone morphogenetic protein-2 (BMP2)-Msx2-dependent calcification. In addition, OPN may enhance cell-mediated release of calcium from vascular deposits.
The first evidence for an involvement of OPG in arterial calcification was derived from OPG knockout mice, which displayed osteoporosis and arterial calcification of the media of the aorta and the renal arteries (36). Moreover, the study by Min and co-workers reported multi-nucleated osteoclast-like cells in the calcified vascular lesions of OPG-deficient mice (37). Finally, systemic administration of OPG has been found to prevent vitamin D-induced vascular calcifications in rodents.
Conclusion and perspectives
Emerging evidence indicates that MPs and CBP are not merely a protective factor for bone or calcium regulators, but may, in fact, act as protective factors for the vascular system and play a crucial role in cardiac remodelling of the stressed heart. Its underline the association between mediators of bone homeostasis and cardiovascular disease and there is evidence to say that CBP and MP could be consider has novel markers for cardiovascular events, heart remodelling, vascular calcifications and predictors of death after cardiac events.
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| المجلد 3 , العدد 8 , جمادى الآخرة 1426 - تموز (يوليو) 2005 |
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