Beta-catenin downregulation is required for adaptive cardiac remodeling.

The armadillo-related protein beta-catenin has multiple functions in cardiac tissue homeostasis: stabilization of beta-catenin has been implicated in adult cardiac hypertrophy, and downregulation initiates heart formation in embryogenesis. The protein is also part of the cadherin/catenin complex at the cell membrane, where depletion might result in disturbed cell-cell interaction similar to N-cadherin knockout models. Here, we analyzed the in vivo role of beta-catenin in adult cardiac hypertrophy initiated by angiotensin II (Ang II). The cardiac-specific mifepristone-inducible alphaMHC-CrePR1 transgene was used to induce beta-catenin depletion (loxP-flanked exons 3 to 6, beta-cat(Deltaex3-6) mice) or stabilization (loxP-flanked exon 3, beta-cat(Deltaex3) mice). Levels of beta-catenin were altered both in membrane and nuclear extracts. Analysis of the beta-catenin target genes Axin2 and Tcf-4 confirmed increased beta-catenin-dependent transcription in beta-catenin stabilized mice. In both models, transgenic mice were viable and healthy at age 6 months. beta-Catenin appeared dispensable for cell membrane function. Ang II infusion induced cardiac hypertrophy both in wild-type mice and in mice with beta-catenin depletion. In contrast, mice with stabilized beta-catenin had decreased cross-sectional area at baseline and an abrogated hypertrophic response to Ang II infusion. Stabilizing beta-catenin led to impaired fractional shortening compared with control littermates after Ang II stimulation. This functional deterioration was associated with altered expression of the T-box proteins Tbx5 and Tbx20 at baseline and after Ang II stimulation. In addition, atrophy-related protein IGFBP5 was upregulated in beta-catenin-stabilized mice. These data suggest that beta-catenin downregulation is required for adaptive cardiac hypertrophy.

Requirement of nuclear factor-kappaB in angiotensin II- and isoproterenol-induced cardiac hypertrophy in vivo.

BACKGROUND: In vitro experiments have proposed a role of nuclear factor-kappaB (NF-kappaB), a transcription factor, in cardiomyocyte hypertrophy and protection against apoptosis. Currently, the net effect on cardiac remodeling in vivo under common stress stimuli is unclear. METHODS AND RESULTS: We have generated mice with cardiomyocyte-restricted expression of the NF-kappaB super-repressor IkappaBalphaDeltaN (DeltaN(MHC)) using the Cre/lox technique. DeltaN(MHC) mice displayed an attenuated hypertrophic response compared with control mice on infusion of angiotensin II (Ang II) or isoproterenol by micro-osmotic pumps, as determined by echocardiography (left ventricular wall dimensions: control plus Ang II, x1.5+/-0.1 versus sham; DeltaN(MHC) plus Ang II, x1.1+/-0.1 versus sham; P<0.05; n> or =9), heart weight, and histological analysis. Real-time reverse-transcriptase polymerase chain reaction showed significantly reduced expression of hypertrophy markers beta-myosin heavy chain and atrial natriuretic peptide in Ang II-treated DeltaN(MHC) mice (P<0.05 versus control plus Ang II; n=4). Neither cardiomyocyte apoptosis nor left ventricular dilatation was observed. In cultured adult rat cardiomyocytes, NF-kappaB DNA binding activity was increased by both Ang II- and interleukin-6-related cytokines. The latter are known to be released by cardiac fibroblasts on Ang II stimulation and thus could locally increase the NF-kappaB response of cardiomyocytes. Finally, results from in vitro and in vivo experiments suggest a role for NF-kappaB in the regulation of prohypertrophic interleukin-6 receptor gp130 on mRNA levels. CONCLUSIONS: These results indicate that targeted inhibition of NF-kappaB in cardiomyocytes in vivo is sufficient to impair Ang II- and isoproterenol-induced hypertrophy without increasing the susceptibility to apoptosis.

[What can experimental research offer to rheumatology today--the viewpoint of molecular biology? Contribution of molecular biology to pathogenesis research in rheumatology using the example of rheumatoid arthritis]. / Was kann die experimentelle Forschung der Rheumatologie heute bieten--die Sichtweise der Molekularbiologie? Beitrag der Molekularbiologie zur Pathogeneseforschung in der Rheumatologie am Beispiel der Rheumatoiden Arthritis.

Molecular biology plays an increasing role for the development of innovative approaches to analyze the pathogenesis of rheumatic diseases and to improve diagnosis and therapy of these disorders. Some of these approaches/techniques have recently yielded important results, e.g. the analysis of 1) chromosomal aberrations (numerical and, in part, structural aberrations in synovial fibroblasts/macrophages from chronic joint inflammation); 2) cell clonality (oligoclonal expansion of synovial T-cells, B-cells, but also fibroblasts); 3) the importance of genetic factors (genome-wide screening for arthritis susceptibility genes); 4) mutations in key genes of cell cycle and/or function (mutations in p53 and proto-oncogenes in the inflamed synovial membrane); and 5) gene expression patterns (e.g. by high-density microarrays, custom arrays, in situ hybridization, and real-time PCR). It can be expected that these analyses will result in central new findings concerning the understanding of the pathogenetic basis of chronic inflammatory rheumatic diseases, with the potential to develop differential diagnostic criteria for these hitherto extremely heterogeneous diseases, and to create the basis for individual-oriented therapy.