Bence Ágg

The role of transforming growth factor-beta in Marfan syndrome

The starting point, in Marfan syndrome (MFS) appears to be the mutation of fibrillin-1 gene whose deconstructed protein product cannot bind transforming growth factor beta (TGF-b), leading to an increased TGF-b tissue level. The aim of this review is to review the already known features of the cellular signal transduction downstream to TGF-b and its impact on the tissue homeostasis of microfibrils, and elastic fibers. We also investigate current data on the extracellular regulation of TGF-b level including mechanotransduction and the feedback cycles of integrin-dependent and independent activation of the latent TGF-b complex. Together these factors, by the destruction of the connective tissue fibers, may play an important role in the development of the diverse cardiac and extracardiac manifestations of MFS and many of them could be a target of conservative treatment. We present currently investigated drugs for the treatment of the syndrome, and explore possible avenues of research into pathogenesis of MFS in order to improve understanding of the disease.

Survival pathways in cardiac conditioning: individual data vs. meta-analyses. What do we learn?

In an elegant study, Kleinbongard et al. [7] developed a strategy for the quantification of protein expression and phosphorylation in multiple tissue samples taken from various experiments on different gels/membranes by Western blot. Here, they analyze “survival signaling” proteins and their phosphorylation in left ventricular biopsies taken from the previous pig studies on ischemic preconditioning (IPC), ischemic postconditioning (POCO), and remote ischemic conditioning (RIPC). They show that neither the expression nor the phosphorylation of the classical protective signaling proteins (AKT, ERK1/2, GSK-3beta, p38 MAPK, or PKG) were associated with reduced infarct size by different conditioning strategies, and that only STAT3 phosphorylation (when normalized to total STAT3 expression) was consistently associated with cardioprotection obtained by ischemic preconditioning but not by the other conditioning strategies. In the light of the lack of successful translation of many preclinical cardioprotection data to clinical therapy, these results might not be surprising [4]. However, given the abundance of preclinical papers (including studies in pigs) claiming that above survival protein kinases are important mediators of ischemic conditioning, one may question the reproducibility of individual preclinical studies/data and ask a more important question, how to move forward in finding valid molecular targets for cardioprotection (see for a recent position paper [3]). What do we learn from the above study by Kleinbongard et al. [7]?

Heterotopic abdominal rat heart transplantation as a model to investigate volume dependency of myocardial remodeling

Abstract Heterotopic abdominal rat heart transplantation has been extensively used to investigate ischemic-reperfusion injury, immunological consequences during heart transplantations and also to study remodeling of the myocardium due to volume unloading. We provide a unique review on the latter and present a summary of the experimental studies on rat heart transplantation to illustrate changes that occur to the myocardium due to volume unloading. We divided the literature based on whether normal or failing rat heart models were used. This analysis may provide a basis to understand the physiological effects of mechanical circulatory support therapy.

MicroRNA interactome analysis predicts post-transcriptional regulation of ADRB2 and PPP3R1 in the hypercholesterolemic myocardium

Little is known about the molecular mechanism including microRNAs (miRNA) in hypercholesterolemia-induced cardiac dysfunction. We aimed to explore novel hypercholesterolemia-induced pathway alterations in the heart by an unbiased approach based on miRNA omics, target prediction and validation. With miRNA microarray we identified forty-seven upregulated and ten downregulated miRNAs in hypercholesterolemic rat hearts compared to the normocholesterolemic group. Eleven mRNAs with at least 4 interacting upregulated miRNAs were selected by a network theoretical approach, out of which 3 mRNAs (beta-2 adrenergic receptor [Adrb2], calcineurin B type 1 [Ppp3r1] and calcium/calmodulin-dependent serine protein kinase [Cask]) were validated with qRT-PCR and Western blot. In hypercholesterolemic hearts, the expression of Adrb2 mRNA was significantly decreased. ADRB2 and PPP3R1 protein were significantly downregulated in hypercholesterolemic hearts. The direct interaction of Adrb2 with upregulated miRNAs was demonstrated by luciferase reporter assay. Gene ontology analysis revealed that the majority of the predicted mRNA changes may contribute to the hypercholesterolemia-induced cardiac dysfunction. In summary, the present unbiased target prediction approach based on global cardiac miRNA expression profiling revealed for the first time in the literature that both the mRNA and protein product of Adrb2 and PPP3R1 protein are decreased in the hypercholesterolemic heart.

Author Correction: MicroRNA interactome analysis predicts post-transcriptional regulation of ADRB2 and PPP3R1 in the hypercholesterolemic myocardium

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Hungarian Marfan family with large FBN1 deletion calls attention to copy number variation detection in the current NGS era

Copy number variations (CNVs) comprise about 10% of reported disease-causing mutations in Mendelian disorders. Nevertheless, pathogenic CNVs may have been under-detected due to the lack or insufficient use of appropriate detection methods. In this report, on the example of the diagnostic odyssey of a patient with Marfan syndrome (MFS) harboring a hitherto unreported 32-kb FBN1 deletion, we highlight the need for and the feasibility of testing for CNVs (>1 kb) in Mendelian disorders in the current next-generation sequencing (NGS) era.

Prophilactic aortic-root reconstruction in Marfan syndrome

of these excellent results is even more contrasted the 49% five year survival rate in the AAD group, not mentioned it’s 21% hospital lethality. The only conclusion might be taken out of these results: the prophylactic aortic root reconstruction is a safe and useful method, connected with excellent long term survival to prevent the occurrence of AAD.

Successful heart transplantation as third cardiac operation in a 12 year-old Marfan patient

Background Approximately 300.000 patients might be treated in Hungary because of heart failure. Out of this 900-1000 might be affected by end stage heart failure. These patients should be potentially treated by heart transplantation (HTX). The etiologic reasons of heart failure among transplanted patient are mainly cardiomyopathic or ischemic in origin (48%-44%). The valvular or congenital origin is rear (4%-2%). The prevalence of Marfan syndrome is 1-2/ 10.000; it means that we can calculate with 1000-2000 Marfan patients (MP) in Hungary. As it is mentioned in the literature MPs are often affected by a left ventricle dysfunction due to the characteristic Marfan cardiomyopathy, which may show a rapid progression in case of concomitant longstanding aortic or/and mitral regurgitation.