Insulin sensitivity in the aged heart is improved by down-regulation of KAT7 in vivo and in vitro

AbstractLINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, middle cerebral artery occlusion/reperfusion (MACO/R) mice model and HT22 cell oxygen–glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of cerebral ischemia in vivo and in vitro and to detect the relevant mechanism. We found that LINGO-1 mRNA and protein were upregulated in mice and cell models. Down-regulation LINGO-1 improved the neurological symptoms and reduced pathological changes and the infarct size of the mice after MACO/R. In addition, LINGO-1 interference alleviated apoptosis and promoted cell proliferation in HT22 of OGD/R. Moreover, down-regulation of LINGO-1 proved to inhibit nuclear translocation of p-NF-κB and reduce the expression level of p-JAK2 and p-STAT3. In conclusion, our data suggest that shLINGO-1 attenuated ischemic injury by negatively regulating NF-KB and JAK2/STAT3 pathways, highlighting a novel therapeutic target for ischemic stroke.

Download Full-text

GDNF and neurturin are target-derived factors essential for cranial parasympathetic neuron development

Development ◽

10.1242/dev.128.19.3773 ◽

2001 ◽

Vol 128 (19) ◽

pp. 3773-3782 ◽

Cited By ~ 1

Author(s):

Eri Hashino ◽

Marlene Shero ◽

Dirk Junghans ◽

Hermann Rohrer ◽

Jeffrey Milbrandt ◽

...

Keyword(s):

Striate Muscle ◽

Ciliary Ganglion ◽

Neuron Development ◽

Down Regulation ◽

Eye Muscle ◽

Ciliary Ganglion Neurons ◽

Ganglion Neurons ◽

Parasympathetic Neuron

During development, parasympathetic ciliary ganglion neurons arise from the neural crest and establish synaptic contacts on smooth and striate muscle in the eye. The factors that promote the ciliary ganglion pioneer axons to grow toward their targets have yet to be determined. Here, we show that glial cell line-derived neurotrophic factor (GDNF) and neurturin (NRTN) constitute target-derived factors for developing ciliary ganglion neurons. Both GDNF and NRTN are secreted from eye muscle located in the target and trajectory pathway of ciliary ganglion pioneer axons during the period of target innervation. After this period, however, the synthesis of GDNF declines markedly, while that of NRTN is maintained throughout the cell death period. Furthermore, both in vitro and in vivo function-blocking of GDNF at early embryonic ages almost entirely suppresses ciliary axon outgrowth. These results demonstrate that target-derived GDNF is necessary for ciliary ganglion neurons to innervate ciliary muscle in the eye. Since the down-regulation of GDNF in the eye is accompanied by down-regulation of GFRα1 and Ret, but not of GFRα2, in innervating ciliary ganglion neurons, the results also suggest that target-derived GDNF regulates the expression of its high-affinity coreceptors.

Download Full-text

Down regulation of in vivo and in vitro T cell responses post cytomegalovirus immune globulin intravenous (human) administration in sensitized renal transplant candidates

Transplantation Proceedings ◽

10.1016/s0041-1345(98)02035-1 ◽

1999 ◽

Vol 31 (1-2) ◽

pp. 1378-1381 ◽

Cited By ~ 3

Author(s):

K.S.R SivaSai ◽

T Mohanakumar ◽

D Phelan ◽

S Martin ◽

M.E Anstey ◽

...

Keyword(s):

T Cell ◽

Renal Transplant ◽

Immune Globulin ◽

T Cell Responses ◽

Down Regulation ◽

Cell Responses ◽

Transplant Candidates

Download Full-text

The Antidepressant Desipramine Is an Arrestin-biased Ligand at the α2A-Adrenergic Receptor Driving Receptor Down-regulation in Vitro and in Vivo

Journal of Biological Chemistry ◽

10.1074/jbc.m111.261578 ◽

2011 ◽

Vol 286 (41) ◽

pp. 36063-36075 ◽

Cited By ~ 33

Author(s):

Christopher Cottingham ◽

Yunjia Chen ◽

Kai Jiao ◽

Qin Wang

Keyword(s):

Adrenergic Receptor ◽

Antidepressant Drug ◽

Antidepressant Drugs ◽

Direct Interaction ◽

Receptor Expression ◽

Receptor Internalization ◽

Down Regulation ◽

Altered Expression

The neurobiological mechanisms of action underlying antidepressant drugs remain poorly understood. Desipramine (DMI) is an antidepressant classically characterized as an inhibitor of norepinephrine reuptake. Available evidence, however, suggests a mechanism more complex than simple reuptake inhibition. In the present study, we have characterized the direct interaction between DMI and the α2A-adrenergic receptor (α2AAR), a key regulator of noradrenergic neurotransmission with altered expression and function in depression. DMI alone was found to be sufficient to drive receptor internalization acutely and a robust down-regulation of α2AAR expression and signaling following prolonged stimulation in vitro. These effects are achieved through arrestin-biased regulation of the receptor, as DMI selectively induces recruitment of arrestin but not activation of heterotrimeric G proteins. Meanwhile, a physiologically relevant concentration of endogenous agonist (norepinephrine) was unable to sustain a down-regulation response. Prolonged in vivo administration of DMI resulted in significant down-regulation of synaptic α2AAR expression, a response that was lost in arrestin3-null animals. We contend that direct DMI-driven arrestin-mediated α2AAR down-regulation accounts for the therapeutically desirable but mechanistically unexplained adaptive alterations in receptor expression associated with this antidepressant. Our results provide novel insight into both the pharmacology of this antidepressant drug and the targeting of the α2AAR in depression.

Download Full-text

Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00219.2021 ◽

2021 ◽

Author(s):

Rui Shang ◽

Nathaniel Lal ◽

ChaeSyng Lee ◽

Yajie Zhai ◽

Karanjit Puri ◽

...

Keyword(s):

Insulin Sensitivity ◽

Lipoprotein Lipase ◽

Insulin Action ◽

Insulin Signalling ◽

Isolated Heart ◽

Cardiac Metabolism ◽

Metabolic Reprogramming ◽

Flux Analysis

Cardiac muscle utilizes multiple sources of energy including glucose and fatty acid (FA). The heart cannot synthesize FA and relies on obtaining it from other sources, with lipoprotein lipase (LPL) breakdown of lipoproteins suggested to be a key source of FA for cardiac use. Recent work has indicated that cardiac vascular endothelial growth factor B (VEGFB) overexpression expands the coronary vasculature and facilitates metabolic reprogramming that favours glucose utilization. We wanted to explore whether this influence of VEGFB on cardiac metabolism involves regulation of LPL activity with consequent effects on lipotoxicity and insulin signalling. The transcriptomes of rats with and without cardiomyocyte-specific overexpression of human VEGFB were compared by using RNA-sequencing. Isolated perfused hearts or cardiomyocytes incubated with heparin were used to enable measurement of LPL activity. Untargeted metabolomic analysis was performed for quantification of cardiac lipid metabolites. Cardiac insulin sensitivity was evaluated using fast-acting insulin. Isolated heart and cardiomyocytes were used to determine transgene-encoded VEGFB isoform secretion patterns and mitochondrial oxidative capacity using high-resolution respirometry and extracellular flux analysis. In vitro, primary transgenic cardiomyocytes incubated overnight and thus exposed to abundantly secreted VEGFB isoforms in the absence of any in vivo confounding regulators of cardiac metabolism demonstrated higher basal oxygen consumption. In the whole heart, VEGFB overexpression induced an angiogenic response that was accompanied by limited cardiac LPL activity through multiple mechanisms. This was associated with a lowered accumulation of lipid intermediates, diacylglycerols and lysophosphatidylcholine, that are known to influence insulin action. In response to exogenous insulin, transgenic hearts demonstrated increased insulin sensitivity. In conclusion, the interrogation of VEGFB function on cardiac metabolism uncovered an intriguing and previously unappreciated effect to lower LPL activity and prevent lipid metabolite accumulation to improve insulin action. VEGFB could be a potential cardioprotective therapy to treat metabolic disorders, for example diabetes.

Download Full-text

Down-regulation of heparanase leads to the inhibition of invasion and proliferation of A549 cells in vitro and in vivo

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gms109 ◽

2012 ◽

Vol 45 (3) ◽

pp. 188-193 ◽

Cited By ~ 2

Author(s):

Z. Chen ◽

L. Zhu ◽

X. Li ◽

H. Tian ◽

Y. Fang ◽

...

Keyword(s):

A549 Cells ◽

Down Regulation

Download Full-text

Down regulation of BRCA2 causes radio-sensitization of human tumor cells in vitro and in vivo

Cancer Science ◽

10.1111/j.1349-7006.2008.00741.x ◽

2008 ◽

Vol 99 (4) ◽

pp. 810-815 ◽

Cited By ~ 15

Author(s):

Dong Yu ◽

Emiko Sekine ◽

Akira Fujimori ◽

Takahiro Ochiya ◽

Ryuichi Okayasu

Keyword(s):

Tumor Cells ◽

Human Tumor ◽

Human Tumor Cells ◽

Down Regulation

Download Full-text

Requirement for Down-Regulation of the CCAAT-binding Activity of the NF-Y Transcription Factor during Skeletal Muscle Differentiation

Molecular Biology of the Cell ◽

10.1091/mbc.e02-09-0600 ◽

2003 ◽

Vol 14 (7) ◽

pp. 2706-2715 ◽

Cited By ~ 51

Author(s):

Aymone Gurtner ◽

Isabella Manni ◽

Paola Fuschi ◽

Roberto Mantovani ◽

Fiorella Guadagni ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Cells ◽

Cyclin B1 ◽

Binding Activity ◽

Down Regulation ◽

Cardiac Muscle Cells ◽

Differentiated Cells ◽

Target Promoters

NF-Y is composed of three subunits, NF-YA, NF-YB, and NF-YC, all required for DNA binding. All subunits are expressed in proliferating skeletal muscle cells, whereas NF-YA alone is undetectable in terminally differentiated cells in vitro. By immunohistochemistry, we show that the NF-YA protein is not expressed in the nuclei of skeletal and cardiac muscle cells in vivo. By chromatin immunoprecipitation experiments, we demonstrate herein that NF-Y does not bind to the CCAAT boxes of target promoters in differentiated muscle cells. Consistent with this, the activity of these promoters is down-regulated in differentiated muscle cells. Finally, forced expression of the NF-YA protein in cells committed to differentiate leads to an impairment in the down-regulation of cyclin A, cyclin B1, and cdk1 expression and is accompanied by a delay in myogenin expression. Thus, our results indicate that the suppression of NF-Y function is of crucial importance for the inhibition of several cell cycle genes and the induction of the early muscle-specific program in postmitotic muscle cells.

Download Full-text