Related Experiment Videos

Thromboxane A2 receptor activates a Rho-associated kinase/LKB1/PTEN pathway to attenuate endothelium insulin

Ping Song1, Miao Zhang1, Shuangxi Wang1

  • 1From the Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.

The Journal of Biological Chemistry
|May 1, 2009
PubMed

Insights

Thromboxane A2 receptor (TP) activation in endothelial cells triggers insulin resistance by up-regulating PTEN phosphatase activity, inhibiting key insulin signaling proteins like Akt and eNOS. This pathway is implicated in diet-induced diabetes.

Area of Science:

  • Vascular Biology
  • Endocrinology
  • Molecular Medicine

Background:

  • Insulin resistance in endothelial cells contributes to cardiovascular complications.
  • Thromboxane A2 receptor (TP) signaling plays a role in vascular homeostasis.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which TP activation leads to insulin resistance in endothelial cells.
  • To identify the signaling pathways involved in TP-mediated suppression of insulin signaling.

Main Methods:

  • Utilized human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells.
  • Administered TP mimetics (IBOP, U46619) and assessed insulin-stimulated phosphorylation of Akt and eNOS.
  • Investigated the role of PTEN, Rho GTPase, and G(i) proteins using pharmacological and genetic approaches.
  • Examined signaling in a mouse model of high-fat diet-induced diabetes.

Main Results:

  • TP activation significantly reduced insulin-stimulated Akt and eNOS phosphorylation.
  • TP stimulation led to PTEN up-regulation, increased PTEN phosphorylation, and enhanced PTEN activity.
  • Inhibition of PTEN or Rho-associated kinase restored insulin signaling.
  • TP activation involved G(i) proteins, and these molecular changes were observed in diet-induced diabetic mice.
  • TP antagonist administration reversed these detrimental effects in vivo.

Conclusions:

  • TP stimulation impairs endothelial insulin signaling via the Rho/Rho-associated kinase/LKB1/PTEN pathway.
  • This mechanism contributes to insulin resistance in vascular endothelium, particularly in conditions like diet-induced diabetes.
  • Targeting the TP pathway may offer therapeutic potential for managing vascular insulin resistance.

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Insulin: The Receptor and Signaling Pathways01:28

Insulin: The Receptor and Signaling Pathways

Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but this inhibition is released...
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...