Dataset Information

Heparin-binding EGF-like growth factor induces heart interstitial fibrosis via an Akt/mTor/p70s6k pathway.

ABSTRACT: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is essential for maintaining normal function of the adult heart and is known to play an important role in myocardial remodeling. In the present study, we observed that heart-specific HB-EGF transgenic (TG) mice had systolic dysfunction with decreased fractional shortening (FS%), increased end-systolic diameter (LVIDs) at 5 months of age, increased heart fibrosis, and increased mRNA expression of Col1?1 and Col3?1 at 1, 3, 5 and 7 months of age compared to nontransgenic (NTG) littermates. However, the left ventricular anterior wall thickness at end-systole (LVAWs) of the TG mice was not different than the NTG mice. Phosphorylation levels of Akt, mTor and p70s6k were increased due to HB-EGF expression in TG mice compared with the NTG mice at 3 and 7 months of age. Additionally, activated Akt, mTor and p70s6k were co-localized with vimentin to cardiac fibroblasts isolated from TG mice. Furthermore, HB-EGF significantly increased phosphorylation levels of Akt, mTor and p70s6k and increased expression of type I collagen in cultured primary cardiac fibroblasts. Rapamycin (Rapa) and CRM197, inhibitors of mTor and HB-EGF respectively, could inhibit the expression of type I collagen in the cultured primary cardiac fibroblasts and Rapa suppressed interstitial fibrosis of the heart tissues in vivo. In addition, a BrdU assay showed that HB-EGF increased proliferation of cardiac fibroblasts by 30% compared with cells without HB-EGF treatment. HB-EGF-induced proliferation was completely diminished in the presence of Rapa. These results suggest that HB-EGF induced heart fibrosis and proliferation of cardiac fibroblasts occurs through activation of the Akt/mTor/p70s6k pathway.

SUBMITTER: Lian H

PROVIDER: S-EPMC3440333 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Heparin-binding EGF-like growth factor induces heart interstitial fibrosis via an Akt/mTor/p70s6k pathway.

Lian Hong H Ma Yuanwu Y Feng Juan J Dong Wei W Yang Qing Q Lu Dan D Zhang Lianfeng L

PloS one 20120912 9

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is essential for maintaining normal function of the adult heart and is known to play an important role in myocardial remodeling. In the present study, we observed that heart-specific HB-EGF transgenic (TG) mice had systolic dysfunction with decreased fractional shortening (FS%), increased end-systolic diameter (LVIDs) at 5 months of age, increased heart fibrosis, and increased mRNA expression of Col1α1 and Col3α1 at 1, 3, 5 and ...[more]

PMID: 22984591

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Project description:The purpose of this study was to examine whether insulin-like growth factor (IGF-1) and Akt/mTOR/p70S6K pathway activity is altered by chronic eccentric exercise in rat medial gastrocnemius muscle. Male Wistar rats (n = 24) were randomly assigned to 1 of the 2 groups: eccentric exercise (ECC) group or sham-operated control (CON) group. Rats in the ECC group were trained every second day for 10 days (5 sessions in total) or 20 days (10 sessions in total). After either 5 or 10 exercise sessions, muscle specimens were dissected and weighed. The mRNA expression of IGF-1 and its variant, mechano growth factor (MGF), was evaluated using real time reverse transcriptase-polymerase chain reaction (RT-PCR). Tissue concentrations of Akt (P), mTOR (P), and p70S6K (P) were measured by using western blot analysis. The medial gastrocnemius muscle mass of the ECC group did not show any significant difference after 5 exercise sessions, whereas the muscle mass increased significantly after 10 exercise sessions with a concomitant increase in the cross-sectional area of muscle fibers (p < 0.05). The expression of IGF-1 mRNA and the tissue concentrations of Akt (P) and p70S6K (P) after 10 exercise sessions was significantly higher than those of the age-matched controls and the rats that received 5 exercise sessions. The expression of MGF mRNA in both ECC5S and ECC10S were significantly higher than that in each period-matched control (p < 0.01). The tissue concentration of mTOR (P) after 10 sessions showed a significant increase when compared with period-matched controls (p < 0.01). These results suggest that activation of the IGF-1/Akt/mTOR/p70S6K signaling pathway becomes dominant in the later phase of chronic exercise, when significant muscular hypertrophy is observed. Key pointsWe confirmed that the rat muscular exercise model using originally-developed equipment increased the wet mass of the medial gastrocnemius muscle and cross-sectional areas of muscle fibres in 10 sessions (20 days) but not in 5 sessions (10days).We clarified that the increases of muscle mass and CSA of muscle fibers were accompanied by IGF-1 mRNA expression, the phosphorylated Akt, mTOR, and p70S6K.These results suggest that muscular hypertrophy in our model was achieved after 10 sessions of exercise and associated with the activation of IGF-1/Akt/mTOR/p70S6K signal pathway.

Dataset Information

Heparin-binding EGF-like growth factor induces heart interstitial fibrosis via an Akt/mTor/p70s6k pathway.

Publications

Heparin-binding EGF-like growth factor induces heart interstitial fibrosis via an Akt/mTor/p70s6k pathway.

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