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?-Arrestins regulate human cardiac fibroblast transformation and collagen synthesis in adverse ventricular remodeling.

ABSTRACT: Cardiac fibroblasts (CFs) produce and degrade the myocardial extracellular matrix and are critical in maladaptive ventricular remodeling that can result in heart failure (HF). ?-Arrestins are important signaling molecules involved in ?-adrenergic receptor (?-AR) desensitization and can also mediate signaling in a G protein-independent fashion. We hypothesize that ?-arrestins play an important role in the regulation of adult human CF biology with regard to myofibroblast transformation, increased collagen synthesis, and myocardial fibrosis which are important in the development of HF. ?-Arrestin1 & 2 expression is significantly upregulated in adult human CF isolated from failing left ventricles and ?-AR signaling is uncoupled with loss of ?-agonist-mediated inhibition of collagen synthesis versus normal control CF. Knockdown of either ?-arrestin1 or 2 restored ?-AR signaling and ?-agonist mediated inhibition of collagen synthesis. Overexpression of ?-arrestins in normal CF led to a failing phenotype with increased baseline collagen synthesis, impaired ?-AR signaling, and loss of ?-agonist-mediated inhibition of collagen synthesis. ?-Arrestin knockdown in failing CF diminished TGF-? stimulated collagen synthesis and also inhibited ERK phosphorylation. Overexpression of ?-arrestins in normal CF increased basal ERK1/2 and Smad2/3 phosphorylation and enhanced TGF-?-stimulated collagen synthesis. This was prevented by pre-treatment with a MEK1/2 inhibitor. Enhanced ?-arrestin signaling appears to be deleterious in CF by promoting a pro-fibrotic phenotype via uncoupling of ?-AR signaling as well as potentiating ERK and Smad signaling. Targeted inhibition of ?-arrestins in CF may represent a therapeutic strategy to prevent maladaptive myocardial fibrosis.

SUBMITTER: Li J

PROVIDER: S-EPMC4250404 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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β-Arrestins regulate human cardiac fibroblast transformation and collagen synthesis in adverse ventricular remodeling.

Li Jinju J Philip Jennifer L JL Xu Xianyao X Theccanat Tiju T Abdur Razzaque M M Akhter Shahab A SA

Journal of molecular and cellular cardiology 20140815

Cardiac fibroblasts (CFs) produce and degrade the myocardial extracellular matrix and are critical in maladaptive ventricular remodeling that can result in heart failure (HF). β-Arrestins are important signaling molecules involved in β-adrenergic receptor (β-AR) desensitization and can also mediate signaling in a G protein-independent fashion. We hypothesize that β-arrestins play an important role in the regulation of adult human CF biology with regard to myofibroblast transformation, increased ...[more]

PMID: 25134464

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Project description:Involvement of the Toll-like receptor 4 (TLR4) in maladaptive cardiac remodeling and heart failure (HF) upon pressure overload has been studied extensively, but less is known about the role of TLR2. Interplay and redundancy of TLR4 with TLR2 have been reported in other organs but were not investigated during cardiac dysfunction. We explored whether TLR2 deficiency leads to less adverse cardiac remodeling upon chronic pressure overload and whether TLR2 and TLR4 additively contribute to this. We subjected 35 male C57BL/6J mice (wildtype (WT) or TLR2 knockout (KO)) to sham or transverse aortic constriction (TAC) surgery. After 12 weeks, echocardiography and electrocardiography were performed, and hearts were extracted for molecular and histological analysis. TLR2 deficiency (n = 14) was confirmed in all KO mice by PCR and resulted in less hypertrophy (heart weight to tibia length ratio (HW/TL), smaller cross-sectional cardiomyocyte area and decreased brain natriuretic peptide (BNP) mRNA expression, p < 0.05), increased contractility (QRS and QTc, p < 0.05), and less inflammation (e.g., interleukins 6 and 1β, p < 0.05) after TAC compared to WT animals (n = 11). Even though TLR2 KO TAC animals presented with lower levels of ventricular TLR4 mRNA than WT TAC animals (13.2 ± 0.8 vs. 16.6 ± 0.7 mg/mm, p < 0.01), TLR4 mRNA expression was increased in animals with the largest ventricular mass, highest hypertrophy, and lowest ejection fraction, leading to two distinct groups of TLR2 KO TAC animals with variations in cardiac remodeling. This variation, however, was not seen in WT TAC animals even though heart weight/tibia length correlated with expression of TLR4 in these animals (r = 0.078, p = 0.005). Our data suggest that TLR2 deficiency ameliorates adverse cardiac remodeling and that ventricular TLR2 and TLR4 additively contribute to adverse cardiac remodeling during chronic pressure overload. Therefore, both TLRs may be therapeutic targets to prevent or interfere in the underlying molecular processes.

Dataset Information

?-Arrestins regulate human cardiac fibroblast transformation and collagen synthesis in adverse ventricular remodeling.

Publications

β-Arrestins regulate human cardiac fibroblast transformation and collagen synthesis in adverse ventricular remodeling.

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