Today, dilated cardiomyopathy (DCM) represents the main cause of severe heart failure and disability in younger adults and thus is a challenge for public health. About 30% of DCM cases are genetic in origin; however, the large majority of cases are sporadic, and a viral or immune pathogenesis is suspected. Following the established postulates for pathogenesis of autoimmune diseases, here we provide direct evidence that an autoimmune attack directed against the cardiac β 1 -adrenergic receptor may play a causal role in DCM. First, we immunized inbred rats against the second extracellular β 1 -receptor loop (β 1 -EC II ; 100% sequence identity between human and rat) every month. All these rats developed first, receptorstimulating anti-β 1 -EC II Ab's and then, after 9 months, progressive severe left ventricular dilatation and dysfunction. Second, we transferred sera from anti-β 1 -EC II -positive and Ab-negative animals every month to healthy rats of the same strain. Strikingly, all anti-β 1 -EC II -transferred rats also developed a similar cardiomyopathic phenotype within a similar time frame, underlining the pathogenic potential of these receptor Ab's. As a consequence, β 1 -adrenergic receptor-targeted autoimmune DCM should now be categorized with other known receptor Ab-mediated autoimmune diseases, such as Graves disease or myasthenia gravis. Although carried out in an experimental animal model, our findings should further encourage the development of therapeutic strategies that combat harmful anti-β 1 -EC II in receptor Ab-positive DCM patients.Nonstandard abbreviations used: β1-adrenergic receptor (β1-AR); β1-AR second extracellular receptor loop (β1-ECII); body weight (BW); cAMP-dependent protein kinase (PKA); cardiac output (CO); dilated cardiomyopathy (DCM); glutathione-Stransferase (GST); human embryonal kidney (HEK); immunofluorescence microscopy (IFM); 125 I-labeled cyanopindolol ([ 125 I]-CYP); isobutylmethylxanthine (IBMX); left ventricular (LV); LV end-diastolic diameter (LVED); LV end-diastolic pressure (LVEDP); LV area (LVA); LV cavity area (LVCA); LV wall area (LVWA); peak change in LV pressure per time (interval) (dp/dtmax); velocity-time integral (VTI).

Today, dilated cardiomyopathy (DCM) represents the main cause of severe heart failure and disability in younger adults and thus is a challenge for public health. About 30% of DCM cases are genetic in origin; however, the large majority of cases are sporadic, and a viral or immune pathogenesis is suspected. Following the established postulates for pathogenesis of autoimmune diseases, here we provide direct evidence that an autoimmune attack directed against the cardiac β 1 -adrenergic receptor may play a causal role in DCM. First, we immunized inbred rats against the second extracellular β 1 -receptor loop (β 1 -EC II ; 100% sequence identity between human and rat) every month. All these rats developed first, receptorstimulating anti-β 1 -EC II Ab's and then, after 9 months, progressive severe left ventricular dilatation and dysfunction. Second, we transferred sera from anti-β 1 -EC II -positive and Ab-negative animals every month to healthy rats of the same strain. Strikingly, all anti-β 1 -EC II -transferred rats also developed a similar cardiomyopathic phenotype within a similar time frame, underlining the pathogenic potential of these receptor Ab's. As a consequence, β 1 -adrenergic receptor-targeted autoimmune DCM should now be categorized with other known receptor Ab-mediated autoimmune diseases, such as Graves disease or myasthenia gravis. Although carried out in an experimental animal model, our findings should further encourage the development of therapeutic strategies that combat harmful anti-β 1 -EC II in receptor Ab-positive DCM patients.Nonstandard abbreviations used: β1-adrenergic receptor (β1-AR); β1-AR second extracellular receptor loop (β1-ECII); body weight (BW); cAMP-dependent protein kinase (PKA); cardiac output (CO); dilated cardiomyopathy (DCM); glutathione-Stransferase (GST); human embryonal kidney (HEK); immunofluorescence microscopy (IFM); 125 I-labeled cyanopindolol ([ 125 I]-CYP); isobutylmethylxanthine (IBMX); left ventricular (LV); LV end-diastolic diameter (LVED); LV end-diastolic pressure (LVEDP); LV area (LVA); LV cavity area (LVCA); LV wall area (LVWA); peak change in LV pressure per time (interval) (dp/dtmax); velocity-time integral (VTI).

Apples (Malus spp., Rosaceae) and products thereof contain high amounts of polyphenols which show diverse biological activities and may contribute to beneficial health effects, like protecting the intestine against inflammation initiated by chronic inflammatory bowel diseases (IBD). IBD are characterized by an excessive release of several proinflammatory cytokines and chemokines by different cell types which results consequently in an increased inflammatory response. In the present study we investigated the preventive effectiveness of polyphenolic juice extracts and single major constituents on inflammatory gene expression in immunorelevant human cell lines (DLD-1, T84, MonoMac6, Jurkat) induced with specific stimuli. Besides the influence on proinflammatory gene expression, the effect on NF-kappaB-, IP-10-, IL-8-promoter-, STAT1-dependent signal transduction, and the relative protein levels of multiple released cytokines and chemokines were studied. DNA microarray analysis of several genes known to be strongly regulated during gastrointestinal inflammation, combined with quantitative real-time PCR (qRT-PCR) revealed that the apple juice extract AE04 (100-200 microg/mL) significantly inhibited the expression of NF-kappaB regulated proinflammatory genes (TNF-alpha, IL-1beta, CXCL9, CXCL10), inflammatory relevant enzymes (COX-2, CYP3A4), and transcription factors (STAT1, IRF1) in LPS/IFN-gamma stimulated MonoMac6 cells without significant effects on the expression of house-keeping genes. A screening of some major compounds of AE04 revealed that the flavan-3-ol dimer procyanidin B(2 )is mainly responsible for the anti-inflammatory activity of AE04. Furthermore, the dihydrochalcone aglycone phloretin and the dimeric flavan-3-ol procyanidin B(1 )significantly inhibited proinflammatory gene expression and repressed NF-kappaB-, IP-10-, IL-8-promoter-, and STAT1-dependent signal transduction in a dose-dependent manner. The influence on proinflammatory gene expression by the applied polyphenols thereby strongly correlated with the increased protein levels investigated by human cytokine array studies. In summary, we evaluated selected compounds responsible for the anti-inflammatory activity of AE04. In particular, procyanidin B(1), procyanidin B(2), and phloretin revealed anti-inflammatory activities in vitro and therefore may serve as transcription-based inhibitors of proinflammatory gene expression.

Studies with nonintestinal models indicate that anthocyanin-rich extracts can modulate inflammatory gene expression and may help prevent development of inflammatory bowel diseases (IBD). This work investigated the influence of a bilberry ( Vaccinium myrtillus L.) extract (BE) and comprising anthocyanins on pro-inflammatory genes in IFN-γ/IL-1β/TNF-α stimulated human colon epithelial cells (T84) by qRT-PCR and cytokine arrays. Moreover, the stability of selected anthocyanins under cell culture conditions was examined to assess their anti-inflammatory properties. BE and single anthocyanins significantly inhibited the expression and secretion of IBD-associated pro-inflammatory mediators (TNF-α, IP-10, I-TAC, sICAM-1, GRO-α) in the stimulated cells. The anti-inflammatory activity thereby strongly depends on the aglycon structure (hydroxylation and methylation pattern) and the sugar moiety. In contrast to anthocyanidins, which were highly unstable in cell culture medium, suggesting that their degradation products might contribute to the inhibitory effects assigned to the parent compounds, anthocyanins have higher stability and may directly contribute to BE's effects.

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