D-Glucose stimulation of L-arginine transport and nitric oxicle 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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Date
2007
Journal Title
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Publisher
WILEY
Abstract
Elevated extracellular D-glucose increases transforming growth factor P I (TGF-P 1) release from human umbilical vein endothelium (HUVEC). TGF-P 1, via TGF-P receptors I (T beta RI) and T beta RII, 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-beta 1 in primary cultures of HUVEC. TGF-P I release was higher (similar to 1.6-fold) in 25 mM (high) compared with 5 mM (normal) D-glucose. TGF-P I increases L-arginine transport (half maximal effect similar to 1.6 ng/ml) in normal D-glucose, but did not alter high D-glucose-increased L-arginine transport. TGF-P I and high D-glucose increased hCAT- I mRNA expression (similar to 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-beta 1 I and high D-gludose increased p42/44 mapk and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK 1 /2 inhibitor). However, TGF-P I and high D-glucose were ineffective in cells expressing a truncated, negative dominant T beta RII High D-glucose increases L-arginine transport and eNOS expression following T beta RII activation by TGF-P I involving p42/44 (mapk) and Smad2 in HUVEC. Thus, TGF-P I could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is
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Keywords
GROWTH-FACTOR-BETA, SMOOTH-MUSCLE-CELLS, OXIDE SYNTHASE EXPRESSION, SIGNAL-REGULATED KINASE, HUMAN MESANGIAL CELLS, AMINO-ACID, ACUTE HYPERGLYCEMIA, VASODILATION, DYSFUNCTION, TGF-BETA-1