Changes in extra cellular matrix remodelling and re-expression of fibronectin and tenascin-C splicing variants in human myocardial tissue of the right atrial auricle: implications for a targeted therapy of cardiovascular diseases using human SIP format antibodies

Abstract

Cardiovascular diseases are accompanied by changes in the extracellular matrix (ECM) including the re-expression of fibronectin and tenascin-C splicing variants. Using human recombinant small immunoprotein (SIP) format antibodies, a molecular targeting of these proteins is of therapeutic interest. Tissue samples of the right atrial auricle from patients with coronary artery disease and valvular heart disease were analysed by PCR based ECM gene expression profiling. Moreover, the re-expression of fibronectin and tenascin-C splicing variants was investigated by immunofluoerescence labelling. We demonstrated changes in ECM gene expression depending on histological damage or underlying cardiac disease. An increased expression of fibronectin and tenascin-C mRNA in association to histological damage and in valvular heart disease compared to coronary artery disease could be shown. There was a distinct re-expression of ED-A containing fibronectin and A1 domain containing tenascin-C detectable with human recombinant SIP format antibodies in diseased myocardium. ED-A containing fibronectin showed a clear vessel positivity. For A1 domain containing tenascin-C, there was a particular positivity in areas of interstitial and perivascular fibrosis. Right atrial myocardial tissue is a valuable model to investigate cardiac ECM remodelling. Human recombinant SIP format antibodies usable for an antibody-mediated targeted delivery of drugs might offer completely new therapeutic options in cardiac diseases.

Correlation between systolic function and presence of myofibroblasts in doxorubicin-induced cardiomyopathy

“…Studies have demonstrated the participation of fibrillar collagen, fibronectin, and phenotypically transformed fibroblasts (myofibroblasts) on myocardial scarring. Changes in number and distribution of these structures affect myocardial complacence, with consequent alteration of systolic and diastolic function (heRPeL et al, 2006;FRANz et al, 2010). Phenotypically transformed fibroblasts (myofibroblasts) are cells responsible for the production of fibronectin and collagen.…”

Tenascin-C in cardiovascular remodeling: potential impact for diagnosis, prognosis estimation and targeted therapy

“…22 In cardiac tissue of patients suffering from coronary artery disease who underwent cardiac surgery for revascularization, a distinct re-occurrence of fetal variants of tenascin-C could be evidenced on the mRNA as well as on the protein level. 8 By comparative analysis of tissue samples taken from different regions within the human heart, in particular the right atrial auricle, which is localized near the right atrium and the left side of the interventricular septum, it could be demonstrated that this reexpression phenomenon occurs in the whole organ. This observation speaks well for the fact that cardiac tissue remodeling is an all-encompassing ischemia induced effect, which is not exclusively restricted to the ischemic area.…”

“…23 Among the different fetal splicing variants of Tenascin-C, especially the A1 domain containing molecule seems to be overexpressed in remodelled human cardiac tissue from patients with coronary artery disease. 8,23 Detailed analysis of the protein deposition patterns of A1 domain containing tenascin-C in human cardiac tissue revealed a spatial association to areas of cardiac interstitial fibrosis as well as vessel structures. The vascular deposition is clearly perivascular on the extra-luminal side of the endothelial basement membrane.…”

“…The vascular deposition is clearly perivascular on the extra-luminal side of the endothelial basement membrane. 8 The extensive re-expression of fetal tenascin-C variants described for ischemic cardiomyopathy is also present in valvular heart diseases, in particular left ventricular hypertrophy due to severe aortic valve stenosis which is the most frequent acquired heart valve disease in humans. 8,23 Besides surgical aortic valve replacement, transcatheter aortic valve implantation (TAVI) is a novel, lessinvasive, strategy to treat patients with aortic stenosis.…”

“…2 Cardiac ECM reorganization entails the re-occurrence of fetal variants of cell adhesion modulating proteins like fibronectin or tenascin-C. Tenascin-C is known to regulate cell adhesion, inflammation and tissue remodeling not only in cardiovascular diseases 3 Different variants of the molecule are generated by alternative splicing of the premRNA 4,5 These variants show a high expression during critical steps of heart development, are virtually absent in healthy adult hearts and become abundantly re-expressed in the diseased myocardium [6][7][8][9][10] (Fig. 2).…”