| 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.
|
Collections
