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INVOLVEMENT OF THE 'TRACTION MODEL' AS TGF-BETA1 ACTIVATION MECHANISM IN THE DEVELOPMENT OF REACTIVE FIBROSIS IN SPONTANEOUSLY HYPERTENSIVE RATS CARDIAC FIBROBLASTS.
Get PDFCardiac reactive fibrosis is a well-known pathological effect derived from arterial hypertension. TGF-β plays a key role in the progression from the inflammation state to the fibrosis process establishment. Nonetheless, only the active form of TGF-β is effective, and this occurs if it is unbound to the latency complex proteins (i.e. Latency Associated Protein, LAP and Latent TGF-β Binding Protein, LTBP.
In vivo and in vitro models of different fibrosis-based pathologies (e.g. pulmonary and dermal fibrosis), have highlighted a novelty in the activation of TGF–β, which occurs not only by proteolysis on latent proteins, which involves enzymes as plasmin, thrombospondin and matrix metalloproteases, but also through a non-proteolytic mechanism, defined by Keski-Oja in 2004 "Traction model". This mechanism consists in specific binding of several integrins (αVβ3, αVβ6 and αVβ5), expressed by myofibroblasts, with LAP and LTBP; contraction forces exerted by myofibroblasts are able to active latent TGF-β.
On the basis of the “traction model” are an initial production of TGF-, the conversion of fibroblast into myofibroblast, the production of α-SMA by myofibroblast and their subsequent contractile activity, the increase in ECM production and, therefore, further TGF- production, in a positive feedback mechanism, able to amplify the fibrotic process progression.
Aims of this study are 1) the development of a more fast and efficient protocol to cardiac fibroblast extraction, 2) the evaluation of possible involvement of LTBP-1 and αVβ5 integrin in development of hypertensive-induced cardiac fibrosis and so 3) the speculation about TGF-β1 mechanical activation by traction in primary cardiac fibroblasts isolated in hypertensive rats
Adaptation and Evolution in a Gravitational Environment — A Theoretical Framework for the Limited Re–Generative Post–Natal Time Window of the Heart in Higher Vertebrates
Get PDFIn the complex interplay between organization of the living matter, natural selection and adaptation, mammals have evolved with limited or no re-generative capabilities of the heart after birth.
The reasons for this apparent flaw is far from being understood, however, they are closely related to the concept of organization and allocation of resources in a hierarchically structured multi-cellular organism with an evolved system of transport and communication, such as the circulation of blood. In humans this flaw may not have been a problem for thousands of years until, in the twentieth century, the increase in life expectancy has given rise to diseases generally less frequent in the first three or four decades of life. Therefore, the significant increase in morbidity and mortality related to cardiovascular disease, seen mainly in Western countries in the last years, has brought to the foreground the problem of cardiac damage and of its repair. In order to develop new therapies for cardiovascular damage aimed at reawakening and, possibly, expanding the limited re-generative capabilities of the heart is necessary to reconsider the basic concept on adaptation and functional reserve allocation in complex organisms
Differentiation of fibroblasts into myofibroblasts during hypertensive-derived cardiac fibrosis is promoted by alpha-v beta-5 integrin-mediated activation of TGF-beta1
No full textIntroduction - TGF-β1 plays a key role in the hypertension-associated cardiac fibrosis by acting on cardiac fibroblast differentiation to produce α-smooth muscle actin (α-SMA)-expressing myofibroblasts. Integrin-mediated mechanotransduction induces TGF-β1 activation via its release from latent TGF-β1 binding protein-1 (LTBP-1). Integrin αvβ5 is expressed in the heart tissue and is known to be involved in the TGF-β1 activation.
Purpose: We tested if the hypertensive stimuli present in a rat model of hypertension were sufficient to elicit TGF-β1 activation by integrin αvβ5-mediated traction.
Methods: Immunohistochemistry and Western blot analyses were conducted on heart tissue from Spontaneously Hypertensive Rats (SHR, n=10) and normotensive Wistar Kyoto rats (WKY, n=10).
Results: SHR heart tissue displayed a greater amount of ECM deposition particularly in the perivascular region. Integrin αvβ5 (Figure 1a-c) and LTBP-1 expression (Figure 1g-i) were also significantly increased in the SHR heart (p<0.05). Moreover, isolated SHR cardiac fibroblasts (± recombinant TGF-β1) were more prone to switch to α-SMA expressing cells in vitro, compared to normotensive
cardiac fibroblasts, and had a statistically significant higher expression of integrin αvβ5 and LTBP-1 (p<0.05, Figure 1f,n).
Conclusions: Hypertension stimulated the upregulation of integrin αvβ5, LTBP-1, α-SMA and TGF-β1. It also promoted ECM deposition, the main defining feature of cardiac fibrosis. These results open future studies on molecular tools targeting integrins in cardiac fibroblasts as a strategy to selectively block integrin-mediated TGF-β1 activation and reduce the progression of the cardiac fibrosis process
Peptidyl-prolyl isomerases : A full cast of critical actors in cardiovascular diseases
Get PDFPeptidyl-prolyl cis-trans-isomerases are a highly conserved family of immunophilins. The three peptidyl-prolyl cis-trans-isomerase subfamilies are cyclophilins, FK-506-binding proteins, and parvulins. Peptidyl-prolyl cis-trans-isomerases are expressed in multiple human tissues and regulate different cellular functions, e.g. calcium handling, protein folding, and gene expression. Moreover, these subfamilies have been shown to be consistently involved in several cardiac and vascular diseases including heart failure, arrhythmias, vascular stenosis, endothelial dysfunction, atherosclerosis, and hypertension. This review provides a concise description of the peptidyl-prolyl cis-trans-isomerases and presents an incisive selection of studies focused on their relationship with cardiovascular diseases
Assessing cytokines' talking patterns following experimental myocardial damage by applying Shannon's information theory
No full textBACKGROUND:
The simultaneous measurement of multiple cytokines in parallel by using multiplex proteome arrays (MPA) is of great interest to understanding the inflammatory response following myocardial infarction; however, since cytokines are pleiotropic and redundant, increase of information throughput (IT) attained by measuring multiple cytokines remain to be determined. We aimed this study to assess the IT of an MPA system designed to assess 8 cytokines - commercially available at the time of the study - serum levels, before (control state) and after experimental myocardial cryoinjury (activated state) in rats.
METHODS:
By assuming that redundant information do not generally increase the IT, we derived Entropy (H) and Redundancy (R) of information by using formulas of Shannon modified accordingly, where a high IT (high H and low R) corresponds to a low level of correlation between cytokines and vice versa for a low IT. The maximum theoretical level of IT and the contribution of each cytokine were also estimated.
RESULTS:
In control state, no significant correlations were found between cytokines showing high IT; on the contrary, in activated state, several significant correlations were found supporting a complex cross-talk pattern between cytokines with low IT. Using as reference the maximum theoretical level of IT, in activated state, H was reduced of 67.0% and R was increased of 77.4% supporting a reduction of IT. Furthermore, the contribution of individual cytokines to H value of MPA was variable: in control state, IL-2 gave the most contribution to H value, conversely during activated state IL-10 gave most contribution. Finally during activated state, IL-1β was the only cytokine strongly correlated with values of all other cytokines, suggesting a crucial role in the inflammatory cascade.
CONCLUSIONS:
Paradoxically, by analyzing an MPA system designed for redundant analytes such as cytokines, translating the Shannon's information theory from the field of communication to biology, the IT system in our model deteriorates during the activation state by increasing its redundancy, showing maximum value of entropy in the control conditions. Finally, the study of the mutual interdependence between cytokines by the contribution to the IT may allow formulating alternative models to describe the inflammatory cascade after myocardial infarction
Cell models of arrhythmogenic cardiomyopathy: advances and opportunities
Get PDFArrhythmogenic cardiomyopathy is a rare genetic disease that is mostly inherited as an autosomal dominant trait. It is associated predominantly with mutations in desmosomal genes and is characterized by the replacement of the ventricular myocardium with fibrous fatty deposits, arrhythmias and a high risk of sudden death. In vitro studies have contributed to our understanding of the pathogenic mechanisms underlying this disease, including its genetic determinants, as well as its cellular, signaling and molecular defects. Here, we review what is currently known about the pathogenesis of arrhythmogenic cardiomyopathy and focus on the in vitro models that have advanced our understanding of the disease. Finally, we assess the potential of established and innovative cell platforms for elucidating unknown aspects of this disease, and for screening new potential therapeutic agents. This appraisal of in vitro models of arrhythmogenic cardiomyopathy highlights the discoveries made about this disease and the uses of these models for future basic and therapeutic research
Inflammation-Angiogenesis Cross-Talk and Endothelial Progenitor Cells: A Crucial Axis in Regenerating Vessels
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Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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