Ock Sangmi, Lee Wang Soo, Ahn Jihyun, Kim Hyun Min, Kang Hyun, Kim Ho-Shik, Jo Daewoong, Abel E Dale, Lee Tae Jin, Kim Jaetaek
Division of Endocrinology and Metabolism (S.O., J.A., H.M.K., J.K.), Department of Internal Medicine, Division of Cardiology (W.S.L.), Department of Internal Medicine, and Departments of Anesthesiology (H.K.) and Pathology (T.J.L.), College of Medicine, Chung-Ang University, Seoul, 156-755, Korea; Department of Biochemistry (H.-S.K.), College of Medicine, The Catholic University of Korea, Seoul, 110-758, Korea; Department of Surgery (D.J.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism (D.A.), University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
Endocrinology. 2016 Jan;157(1):336-45. doi: 10.1210/en.2015-1709. Epub 2015 Oct 15.
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.
胰岛素样生长因子-1受体（IGF-1R）信号传导与心脏肥大和寿命有关。然而，IGF-1R在与年龄相关的心脏重塑中的作用仅得到部分了解。因此，我们试图通过检测2岁雄性心肌细胞特异性IGF-1R基因敲除（CIGF1RKO）小鼠，来确定心肌细胞中IGF-1R的缺失是否可能延缓衰老相关心肌病变的发展。衰老与心脏中IGF-1R表达的诱导有关。在野生型（WT）小鼠中，心肌细胞随年龄增长而肥大。相比之下，CIGF1RKO小鼠中与衰老相关的心脏肥大反应减弱。同时，与老年WT心脏相比，老年CIGF1RKO心脏中的纤维化减少。老年WT心脏中促炎细胞因子如IL-1α、IL-1β、IL-6和核因子κB受体激活剂配体的表达增加，但在老年CIGF1RKO心脏中这种增加减弱。老年WT心脏中Akt的磷酸化增加，但老年CIGF1RKO心脏中未增加。在培养的心肌细胞中，IGF-1诱导衰老，表现为衰老相关β-半乳糖苷酶染色增加，磷酸肌醇3-激酶抑制剂可抑制这种作用。此外，抑制磷酸肌醇3-激酶可显著阻止IGF-1引起的IL-1α、IL-1β、核因子κB受体激活剂配体和p21蛋白表达的增加。这些数据揭示了IGF-1-IGF-1R-Akt信号通路在介导心肌细胞衰老中的重要作用。
