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Identifier 000383731
Title Study of keratin 8/18 intermediate filament network and its relation to cardioprotection
Alternative Title Μελέτη του ενδιάμεσου δικτύου των κερατινών 8/8 και η σχέση του με την προστασία του μυοκαρδιοκυττάρου
Author Φραγκιαδάκης, Κωνσταντίνος
Thesis advisor Καπετανάκη, Γιασεμή
Reviewer Σανούδου, Δέσποινα
Καρδάσης, Δημήτριος
Abstract Despite considerable public awareness and technological advances that foster early diagnosis and aggressive therapeutic interventions for cardiovascular disease, heart failure, a critical unsolved problem. With its prevalence to regard 2% of adults and increasing in the elderly, its mortality to increase , understanding its pathophysiology is necessary. Although current drug therapy of heart failure (dependent on adrenergic system and renin-angiotensin-aldosterone axis blockage) improved symptoms and increased overall survival, the progressive nature of heart failure has not been overcome yet. Consequently, studying parallel signaling pathways and identifying important nodal points in the pathophysiology of cardiomyocyte may increase the effectiveness of treatment and overall survival. Recent studies demonstrate that the role of cardiac cytoskeleton is important both in physiology and pathophysiology of cardiomyocyte. Particular reference has been made on the network of intermediate filament that besides the mechanical role in maintaining cellular integrity, it plays a coordinating role in regulating intracellular functions. Desmin, the muscle specific intermediate filament protein, forms a three dimensional scaffold which links the contractile apparatus to the plasma membrane intercalated disks (IDs), the nucleus and also other membranous cellular organelles. Recently under investigation of the mechanism of cardioprotection provided by the desmin cytoskelleton, it was identified that disruption of the cytoskeleton is a key event in apoptotic cell death pathways. Specifically, overexpression of tumor necrosis factor (TNF- α) in the myocardium of heart failure mice models (MHCsTNF-α) leads to removal of desmin from the intercalated disks (IDs) with destruction of their architecture and accumulating into intracellular aggregates. Thereafter, it was found unexpectedly that desmin deficiency in overexpressing TNFa myocardium (TNF-α desm-/-) rescues desmin null myocardium pathology, preventing heart failure. It is known that desmin deficiency in myocardium (desm-/-) results in mitochondrial dysfunction , cardiomyocyte death , fibrosis, calcification and heart failure. Recently, study of TNF-α desm-/- myocardium revealed ectopic expression of keratin 8/18 in myocardium. Although, K8/18 belong to the family of intermediate filament as desmin, they are expressed in simple epithelial cells. Since keratins 8/18 are intermediate filament proteins (part of the cytoskeleton ) and are characterized by crucial properties like desmin such as regulating cellular integrity, mitochondrial function as well as apoptosis, their investigation is important. The objective of this study is to construct expression vectors of mouse keratins 8/18, study their intermediate network and their characteristics in fibroblasts as well as their association with cardioprotection. In this study it was observed that the keratin 18 stabilizes the expression of keratin 8 and vice versa. Ectopic expression of keratin 8 together with keratin 18 leads to the formation of a filamentous network that surrounds the nucleus, spans the cytoplasm and reaches the periphery. Furthermore, ectopic expression of keratin intermediate network in fibroblasts does not interfere with the natural intermediate filament network of vimentin. In coclusion, the study of the expression of keratin intermediate network in the failing myocardium may reveal cardioprotective mechanisms.
Language English
Subject Heart failure
Keratin 18
Keratin 8
Ενδιάμεσα ινίδια
Καρδιακή ανεπάρκεια
Κερατίνη 18
Κερατίνη 8
Issue date 2014-04-10
Collection   Faculty/Department--School of Medicine--Department of Medicine--Post-graduate theses
  Type of Work--Post-graduate theses
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