Insulin signaling is critical for sinoatrial node maintenance and function.

Insulin and insulin-like growth factor 1 (IGF-1) signaling regulate cellular growth and glucose metabolism in the myocardium. However, their physiological role in the cells of the cardiac conduction system has never been explored. Therefore, we sought to determine the spatiotemporal function of insulin/IGF-1 receptors in the sinoatrial node (SAN).

IGF-1 protects against angiotensin II-induced cardiac fibrosis by targeting αSMA.

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.

RANKL blockade suppresses pathological angiogenesis and vascular leakage in ischemic retinopathy.

Receptor activator of NF-κB ligand (RANKL) is a member of the TNF superfamily. RANKL increases endothelial permeability and induces angiogenesis, suggesting its critical roles in the vasculature. Despite the evidence implicating RANKL in vascular pathology, its role in ischemic retinopathy has not been previously reported.

Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation.

Insulin and insulin-like growth factor (IGF)-1 signaling in the thyroid are thought to be permissive for the coordinated regulation by thyroid-stimulating hormone (TSH) of thyrocyte proliferation and hormone production. However, the integrated role of insulin receptor (IR) and IGF-1 receptor (IGF-1R) in thyroid development and function has not been explored. Here, we generated thyrocyte-specific IR and IGF-1R double knockout (DTIRKO) mice to precisely evaluate the coordinated functions of these receptors in the thyroid of neonates and adults.

Connexin43 and zonula occludens-1 are targets of Akt in cardiomyocytes that correlate with cardiac contractile dysfunction in Akt deficient hearts.

While deletion of Akt1 results in a smaller heart size and Akt2 mice are mildly insulin resistant, Akt1/Akt2 mice exhibit perinatal lethality, indicating a large degree of functional overlap between the isoforms of the serine/threonine kinase Akt. The present study aimed to determine the cooperative contribution of Akt1 and Akt2 on the structure and contractile function of adult hearts. To generate an inducible, cardiomyocyte-restricted Akt2 knockout (KO) model, Akt2 mice were crossed with tamoxifen-inducible MerCreMer transgenic (MCM) mice and germline Akt1 mice to generate the following genotypes:Akt1; Akt2 (WT), Akt2; α-MHC-MCM (iAkt2 KO), Akt1, and Akt1; Akt2; α-MHC-MCM mice (Akt1/iAkt2 KO).

Deletion of IGF-1 Receptors in Cardiomyocytes Attenuates Cardiac Aging in Male Mice.

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.

AMP-activated protein kinase α2 and E2F1 transcription factor mediate doxorubicin-induced cytotoxicity by forming a positive signal loop in mouse embryonic fibroblasts and non-carcinoma cells.

Doxorubicin is one of the most widely used anti-cancer drugs, but its clinical application is compromised by severe adverse effects in different organs including cardiotoxicity. In the present study we explored mechanisms of doxorubicin-induced cytotoxicity by revealing a novel role for the AMP-activated protein kinase α2 (AMPKα2) in mouse embryonic fibroblasts (MEFs). Doxorubicin robustly induced the expression of AMPKα2 in MEFs but slightly reduced AMPKα1 expression.

IGF-1 receptor deficiency in thyrocytes impairs thyroid hormone secretion and completely inhibits TSH-stimulated goiter.

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.

Receptor activator of nuclear factor-κB ligand is a novel inducer of myocardial inflammation.

Aims: Although increased levels of myocardial receptor activator of nuclear factor (NF)-κB ligand (RANKL) have been reported in heart failure, the role of this pathway in mediating activation of inflammatory pathways during myocardial remodelling is less well understood. This study sought to determine the role of myocardial RANKL in regulating cytokine expression.

Methods And Results: A marked increase in RANKL expression occurred as early as 6h following transverse aortic constriction (TAC) in mouse hearts and persisted at 3 and 17 days.

Conditional deletion of insulin receptor in thyrocytes does not affect thyroid structure and function.

Thyroid-stimulating hormone (TSH) is the primary regulator of thyroid growth and function acting via cyclic AMP signaling cascades. In cultured thyrocytes, insulin and/or insulin-like growth factor-1 (IGF-1) are required for mediating thyrocyte proliferation in concert with TSH. To determine the role of insulin signaling in thyroid, growth in vivo, mice with thyrocyte-selective ablation of the insulin receptor (IR) were generated by crossing mice homozygous for a floxed IR allele with transgenic mice in which thyrocyte-specific expression of Cre recombinase was driven by the human thyroid peroxidase (TPO) gene promoter.