IGF-1 receptor (IGF-1R) signaling is implicated in cardiac hypertrophy and longevity. However, the role of IGF-1R in age-related cardiac remodeling is only partially understood. We therefore sought to determine whether the deletion of the IGF-1R in cardiomyocytes might delay the development of aging-associated myocardial pathologies by examining 2-year-old male cardiomyocyte-specific IGF-1R knockout (CIGF1RKO) mice. Aging was associated with the induction of IGF-1R expression in hearts. Cardiomyocytes hypertrophied with age in wild-type (WT) mice. In contrast, the cardiac hypertrophic response associated with aging was blunted in CIGF1RKO mice. Concomitantly, fibrosis was reduced in aged CIGF1RKO compared with aged WT hearts. Expression of proinflammatory cytokines such as IL-1α, IL-1β, IL-6, and receptor activator of nuclear factor-κB ligand was increased in aged WT hearts, but this increase was attenuated in aged CIGF1RKO hearts. Phosphorylation of Akt was increased in aged WT, but not in aged CIGF1RKO, hearts. In cultured cardiomyocytes, IGF-1 induced senescence as demonstrated by increased senescence-associated β-galactosidase staining, and a phosphoinositide 3-kinase inhibitor inhibited this effect. Furthermore, inhibition of phosphoinositide 3-kinase significantly prevented the increase in IL-1α, IL-1β, receptor activator of nuclear factor-κB ligand, and p21 protein expression by IGF-1. These data reveal an essential role for the IGF-1-IGF-1R-Akt pathway in mediating cardiomyocyte senescence.
Although thyroid-stimulating hormone (TSH) is known to be a major regulator of thyroid hormone biosynthesis and thyroid growth, insulin-like growth factor 1 (IGF-1) is required for mediating thyrocyte growth in concert with TSH in vitro. We generated mice with thyrocyte-selective ablation of IGF-1 receptor (TIGF1RKO) to explore the role of IGF-1 receptor signaling on thyroid function and growth. In 5-wk-old TIGF1RKO mice, serum thyroxine (T4) concentrations were decreased by 30% in concert with a 43% down-regulation of the monocarboxylate transporter 8 (MCT8), which is involved in T4 secretion. Despite a 3.5-fold increase in circulating concentrations of TSH, thyroid architecture and size were normal. Furthermore, thyrocyte area was increased by 40% in WT thyroids after 10 d TSH injection, but this effect was absent in TSH-injected TIGF1RKO mice. WT mice treated with methimazole and sodium perchlorate for 2 or 6 wk exhibited pronounced goiter development (2.0 and 5.4-fold, respectively), but in TIGF1RKO mice, goiter development was completely abrogated. These data reveal an essential role for IGF-1 receptor signaling in the regulation of thyroid function and TSH-stimulated goitrogenesis.
Background: Despite the central position in chemotherapy, the clinical application of doxorubicin is compromised by severe adverse effect in different organs. Results: Doxorubicin induces AMPK␣2 transcription, and AMPK␣2 in turn stabilizes E2F1 in non-carcinoma cells. Conclusion: AMPK␣2 and E2F1 mediate cytotoxicity of doxorubicin. Significance: AMPK␣2 might serve as a novel target for alleviating the cytotoxicity of doxorubicin.
Our data demonstrate for the first time that the pressure-overloaded myocardium generates RANKL, which induces TNF-α, IL-1α, and IL-1β production via a RANK-TRAF2/TRAF6-PLC-PKC-NF-κB-mediated autocrine mechanism.
The insulin-like growth factor 1 receptor (IGF-1R) signaling in cardiomyocytes is implicated in physiological hypertrophy and myocardial aging. Although fibroblasts account for a small amount of the heart, they are activated when the heart is damaged to promote cardiac remodeling. However, the role of IGF-1R signaling in cardiac fibroblasts is still unknown. In this study, we investigated the roles of IGF-1 signaling during agonist-induced cardiac fibrosis and evaluated the molecular mechanisms in cultured cardiac fibroblasts. Using an experimental model of cardiac fibrosis with angiotensin II/phenylephrine (AngII/PE) infusion, we found severe interstitial fibrosis in the AngII/PE infused myofibroblast-specific IGF-1R knockout mice compared to the wild-type mice. In contrast, low-dose IGF-1 infusion markedly attenuated AngII-induced cardiac fibrosis by inhibiting fibroblast proliferation and differentiation. Mechanistically, we demonstrated that IGF-1-attenuated AngII-induced cardiac fibrosis through the Akt pathway and through suppression of rho-associated coiled-coil containing kinases (ROCK)2-mediated α-smooth muscle actin (αSMA) expression. Our study highlights a novel function of the IGF-1/IGF-1R signaling in agonist-induced cardiac fibrosis. We propose that low-dose IGF-1 may be an efficacious therapeutic avenue against cardiac fibrosis.
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