D-glucose stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional type II TGF-beta receptors in human umbilical vein endothelium.

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Vasquez R, Farias M, Vega JL, Martin RS, Vecchiola A, Casanello P, Sobrevia L

J Cell Physiol. 2007 Sep;212(3):626-32.

PubMed ID

17427197 [ View in PubMed

]

Abstract

Elevated extracellular D-glucose increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC). TGF-beta1, via TGF-beta receptors I (TbetaRI) and TbetaRII, activates Smad2 and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC. TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) D-glucose. TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal D-glucose, but did not alter high D-glucose-increased L-arginine transport. TGF-beta1 and high D-glucose increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from L-[(3)H]arginine (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter eNOS phosphorylation. TGF-beta1 and high D-glucose increased p42/44(mapk) and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor). However, TGF-beta1 and high D-glucose were ineffective in cells expressing a truncated, negative dominant TbetaRII. High D-glucose increases L-arginine transport and eNOS expression following TbetaRII activation by TGF-beta1 involving p42/44(mapk) and Smad2 in HUVEC. Thus, TGF-beta1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Arginine	High affinity cationic amino acid transporter 1	Protein	Humans	Unknown	Not Available	Details