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Interstitial remodeling in beta1-adrenergic receptor transgenic mice.

ABSTRACT: BACKGROUND: Inhibition of proteolytic MMP activity could be a therapeutic approach to prevent ventricular dilatation by diminishing collagen matrix turnover and interstitial fibrosis. We investigated the time-course of MMP/TIMP activity during transition from hypertrophy to ventricular dilatation in transgenic mice with myocyte overexpression of the human beta1-adrenergic receptor (beta1TG). These beta1TG mice were studied at 3 (normal function), 5 (hypertrophy) and 12 (ventricular dilatation) months of age compared to age-matched controls (WT). METHODS: Picro Sirius red staining and real-time PCR were performed for total collagen and for collagen type I and III quantification, respectively. MMP-activity assays (zymography), immunoblotting and real-time PCR experiments were done for gelatinase- (MMP-2, -9), collagenase- (MMP-1, -13), membrane-type MMP- (MT1- MMP; MMP-14) and TIMP expression measurements. To investigate beta1-integrin activity, integrin-linked kinase (ILK) expression was measured by immunoblotting. RESULTS: Compared to WT with normal cardiac function, interstitial collagen type I and III mRNA and protein expression increased 3.6-fold in beta1TG at 5 months of age with moderate fibrosis and cardiomyocyte hypertrophy and 17-fold in beta1TG at 12 months of age with severe fibrosis and ventricular dilatation. Protein expression of the collagenases MMP-1 and -13 as well as the gelatinase proMMP-2 increased in the beta1TG group with cardiac hypertrophy. Maximal activity of the gelatinase MMP-2 (3.5-fold vs.WT) was measured in beta1TG at 12 months of age with severe fibrosis and ventricular dilatation, accompanied by coexpression of MT1- MMP (3.8-fold vs.WT) colocalized to the cell membranes. CONCLUSION: These data provide evidence that sympathetic overactivation can trigger interstitial matrix remodeling and fibrosis by induction of MMP/TIMP activity. In particular gelatinolytic MMP-2 activity accompanies ventricular dilatation and the development of heart failure.

SUBMITTER: Seeland U

PROVIDER: S-EPMC2779411 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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Interstitial remodeling in beta1-adrenergic receptor transgenic mice.

Seeland Ute U Selejan Simina S Engelhardt Stefan S Müller Patrick P Lohse Martin J MJ Böhm Michael M

Basic research in cardiology 20061124 2

<h4>Background</h4>Inhibition of proteolytic MMP activity could be a therapeutic approach to prevent ventricular dilatation by diminishing collagen matrix turnover and interstitial fibrosis. We investigated the time-course of MMP/TIMP activity during transition from hypertrophy to ventricular dilatation in transgenic mice with myocyte overexpression of the human beta1-adrenergic receptor (beta1TG). These beta1TG mice were studied at 3 (normal function), 5 (hypertrophy) and 12 (ventricular dilata ...[more]

PMID: 17122889

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Project description:The beta1-adrenergic receptor (beta1AR; ADRB1) polymorphism Arg 389Gly is located in an intracellular loop and is associated with distinct human and mouse cardiovascular phenotypes. To test the hypothesis that beta1-Arg389 and beta1-Gly389 alleles could differentially couple to pathways beyond that of classic Gs-adenylyl cyclase (AC)/cAMP signaling, we performed comparative gene expression profile analyses on hearts from wildtype and transgenic mice that expressed either human beta1-Arg389 and beta1-Gly389 receptors, or AC5 adenyl cyclase, sampling at an early age and stage, prior to the onset of pathologic features. We observed substantial overlap of dysregulated genes across all three transgenic heart models, consistent with a shared coupling to cAMP-dependent regulation of cardiac processes and adaptive responses. All three models up-regulated genes associated with RNA metabolism and translation, and down-regulated genes associated with mitochondria and energy metabolism, consistent with cAMP-driven increase in cardiac contractility, protein synthesis, and compensatory down-regulation of mitochondrial energy production. Both beta1AR transgenics activated additional genes associated with kinase-dependent pathways, and uniquely, beta1-Arg389 hearts caused up-regulation of genes associated with inflammation, programmed cell death, and extracellular matrix. These results substantially expand the scope of 7-transmembrane domain receptor signaling propagation beyond known cognate G-protein couplings. Moreover, they implicate alterations of a repertoire of processes evoked by a single amino acid variation in the cardiac beta1AR that might be exploited for genotype-specific heart failure diagnostics and therapeutics. Experiment Overall Design: RNA was isolated from hearts obtained from non-transgenic mice, AC5 transgenic mice, beta1-Gly389 transgenic mice and beta1-Arg389 transgenic mice at 90 days of age. 6 biological replicates were used for each genotype.

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Interstitial remodeling in beta1-adrenergic receptor transgenic mice.

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Interstitial remodeling in beta1-adrenergic receptor transgenic mice.

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