Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
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Query: UMLS:C0028754 (
obesity
)
124,988
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Transient Receptor Potential
Melastatin-2
(TRPM2) is a nonselective cation channel mediating Ca
2+
influx in response to oxidative stress. Given that insulin resistance-related endothelial dysfunction in
obesity
attributes to fatty-acid-induced reactive oxygen species (ROS) overproduction, in this study, we addressed the possible role of TRPM2 in
obesity
-related endothelial insulin resistance and the underlying mechanisms. Whole-cell patch clamp technique, intracellular Ca
2+
concentration measurement, western blot, vasorelaxation assay, and high-fat diet (HFD)-induced obese model were employed to assess the relationship between TRPM2 and endothelial insulin response. We found that both the expression and activity of TRPM2 were higher in endothelial cells of obese mice. Palmitate rose a cationic current in endothelial cells which was inhibited or enlarged by TRPM2 knockdown or overexpression. Silencing of TRPM2 remarkably improved insulin-induced endothelial Akt activation, nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production, while TRPM2 overexpression resulted in the opposite effects. Furthermore, TRPM2-mediated Ca
2+
entry, CaMKII activation and the following activation of PERK/ATF4/TRB3 cascade were involved in the mechanism of
obesity
or palmitate-induced endothelial insulin resistance. Notably, in vivo study, knockdown of TRPM2 with adeno-associated virus harboring short-hairpin RNA (shRNA) against TRPM2 alleviated endothelial insulin resistance and ameliorated endothelium-dependent vasodilatation in obese mice. Thus, these results suggest that TRPM2-activated Ca
2+
signaling is necessary to induce insulin resistance-related endothelial dysfunction in
obesity
. Downregulation or pharmacological inhibition of TRPM2 channels may lead to the development of effective drugs for treatment of endothelial dysfunction associated with oxidative stress state.
...
PMID:Free fatty acid-induced H
2
O
2
activates TRPM2 to aggravate endothelial insulin resistance via Ca
2+
-dependent PERK/ATF4/TRB3 cascade in obese mice. 3144 5
