BRFAA - Biomedical Research Foundation Academy Of Athens
Biomedical Research Foundation Academy Of AthensAcademy Of Athens


The role of innate immunity in the development of heart failure

The role of cytoskeleton in the structure of intercalated discs and their plausible link to the development of dilated cardiomyopathy and arrhythmias

Animal models used


The role of innate immunity in the development of heart failure.

One of the most important therapeutic goals in current cardiology is to determine optimal strategies for the minimization of myocardial necrosis and optimization of cardiac repair following an acute myocardial infarction. We believe that modulating inflammatory reaction could be critical for achieving effective cardiac repair and regeneration. Cardiac tissue injury activates innate immune mechanisms initiating an inflammatory reaction which has a dual role, primarily the repair of the trauma, but eventually enhanced or uncontrolled activation leads to adverse ventricular remodeling with detrimental consequences

We are studying a genetic animal model of heart failure (desmin deficiency) in which extensive cardiomyocyte death and an acute inflammatory reaction is observed early in animal’s life. This reaction is gradually regressed and is followed by a remodelling phase, sharing similarities to acute myocardial infarction. Preliminary data indicate massive complement activation (C3 deposition) and upregulation of complement system components in the myocardium of these mice. To further study the role of complement system in the above cardiac tissue injury animal model we have eliminated three key components of complement cascade activation, the C3 the C5 and the C5a receptor (C5aR) genes, by crossing the corresponding null animals with the desmin null mice. Our results suggest that modulation of the complement cascade could be essential in reducing cardiomyocyte injury, attenuate adverse remodelling and improve cardiac function.

In the desmin null myocardium we also observe a cross talk between the coagulation cascade and complement system activation. Our results indicate that one of the ways by which inhibitors of the coagulation cascade could exert their beneficial effects is by inhibiting complement system activation at the C5 level.
Immediate future objective is to elucidate the underlying molecular mechanisms of these processes and identify targets for intervention. In this context, one area of particular interest is also the investigation of the potential role of complement system components in recruitment of stem cells and/or other type of cells, with “healing” capabilities, at the sites of cardiac tissue injury.

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The role of cytoskeleton in the structure of intercalated discs and their plausible link to the development of dilated cardiomyopathy and arrhythmias.

Cardiomyocytes are mechanically and ionically coupled at the highly specialized cell-cell junctions –the intercalated discs (IDs). It is well documented that intermediated filaments associate with the recently defined “area composita” of the intercalated discs, through desmoplakin. Mutations in desmosomal components of the intercalated discs have been associated with the development of arrhythmogenic right ventricular cardiomyopathy with or without dilated cardiomyopathy (DCM).

The first desmin mutation identified in humans suffering from DCM was the point mutation I451M. In order to elucidate the role of desmin mutations in the development of DCM, we have generated a transgenic animal model that carries this mutation. Analysis of hearts from transgenic animals revealed that mutant desmin loses its z-disc localization but it can still associate with the IDs, which, however, have an altered architecture, resembling other animal models of DCM. Also an unprecedented finding of this study was that this point mutation at the C-terminus leads to cleavage of the N-terminus (head domain) of the protein. This post translational modification (cleavage of head domain) compared to the I451M point mutation, could have a more critical role in the formation of the IF scaffold around z discs and in the structure of IDs.

Currently we study the role of desmin head domain in the structure of IDs, by expressing deletions of desmin head domain in primary cardiomyocytes. Potential observed abnormalities in IDs will guide us to the generation of transgenic animals, as valuable tools in order to study the role of intercalated discs in the development of dilated and or arrhythmogenic cardiomyopathy.
In mammals, each heartbeat is triggered by a single electrical impulse generated in the so-called "pacemaker region" of the sinus node which then is propagated to the atrial and ventricular tissues. At the ultrastructural level typical nodal cells are characterized by their small size and the lowest density of myofilaments showing no ordered organization. The mechanisms involved in the communication and rhythm coordination of large numbers of spontaneously active cells within the node have been the subject of controversy and speculation for many years. We have obtained very interesting results indicating a potential role of intermediate filaments in the structure and function of “elements” connecting the cells of the sinus node, that we call “lateral intercalated discs”. We have been carrying a comparative analysis between wild type and desmin null animals, focusing in the structure and function of these elements and their potential role in the development of cardiac conduction system defects and arrhythmias.

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Animal models used:

Desmin KO mice
Osteopontion KO mice
C3 KO mice
C5 KO mice
C5aR (CD88) KO mice
C5L2 KO mice
TNF transgenic mice
Desmin p. I451M transgenic mice
Desmin p. S13F transgenic mice

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