endothelin-1 and Metabolism--Inborn-Errors

Pediatric obesity is associated with endothelial dysfunction and hypoadiponectinemia, but the relationship between these two conditions remains to be fully clarified. Whether enhanced release of endothelin-1 (ET-1) may directly impair adiponectin (Ad) production in obese children is not known.. The aim of the study was to explore whether and how high circulating levels of ET-1 may contribute to impair Ad production, release, and vascular activity.. Sixty children were included into obese (Ob; n = 30), overweight (OW; n = 11), and lean (n = 19) groups. Total and high-molecular-weight Ad, ET-1, vascular cell adhesion molecule-1, and von Willebrand factor levels were measured in serum samples. Adipocytes were stimulated with exogenous ET-1 or with sera from lean, OW, and Ob, and Ad production and release measured in the absence or in the presence of ETA (BQ-123) and ETB (BQ-788) receptor blockers, p42/44 MAPK inhibitor PD-98059, or c-Jun NH2-terminal protein kinase inhibitor SP-600125. Vasodilation to Ad was evaluated in rat isolated arteries in the absence or in the presence of BQ-123/788.. Total and high-molecular-weight Ad was significantly decreased and ET-1 levels significantly increased in OW (P < .01) and Ob (P < .001) children. A statistically significant linear regression (P < .01) was found between Ad and ET-1. Exposure of adipocytes to exogenous ET-1 or serum from OW and Ob significantly decreased Ad mRNA and protein levels (P < 0.001). The inhibitory effect of ET-1 on Ad was reverted by BQ-123/788 or PD-98059 but not SP-600125. Ad-mediated vasodilation was further increased in arteries pretreated with BQ-123/788.. ET-1-mediated inhibition of Ad synthesis via p42/44 MAPK signaling may provide a possible explanation for hypoadiponectinemia in pediatric obesity and contribute to the development of cardiovascular complications.

Topics: 3T3-L1 Cells; Adiponectin; Age of Onset; Animals; Child; Endothelin-1; Female; Humans; Male; MAP Kinase Signaling System; Metabolism, Inborn Errors; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Obesity; Overweight; Rats; Rats, Wistar; Thinness

Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension. Clinical observation showed that lower plasma adiponectin concentration is significantly associated with hypertension. This study was aimed to determine whether hypoadiponectinemia induces vascular insulin resistance before systemic hypertension and the underlying mechanisms. Four-week-old young spontaneously hypertensive rats (ySHRs, normotensive) and adiponectin knockout (KO; APN(-/-)) mice were used to evaluate the role of hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. ySHRs showed significant vascular insulin resistance as evidenced by the blunted vasorelaxation response to insulin in mesenteric arterioles compared with that of age-matched Wistar-Kyoto controls. Serum adiponectin and mesenteric arteriolar APPL1 (an adaptor protein that mediates adiponectin signaling) expression of ySHRs were significantly reduced. In addition, Akt and endothelial NO synthase phosphorylation and NO production in arterioles were markedly reduced, whereas extracellular signal-regulated protein kinases 1/2 (ERK1/2) phosphorylation and endothelin-1 secretion were augmented in ySHRs. APN(-/-) mice showed significantly decreased APPL1 expression and vasodilation evoked by insulin. More importantly, treatment of ySHRs in vivo with the globular domain of adiponectin for 1 week increased APPL1 expression and insulin-induced vasodilation, and restored the balance between insulin-stimulated endothelial vasodilator NO and vasoconstrictor endothelin-1. In cultured human umbilical vein endothelial cells, globular domain of adiponectin upregulated APPL1 expression. Suppression of APPL1 expression with small interfering RNA markedly blunted the globular domain of adiponectin-induced insulin sensitization as evidenced by reduced Akt/endothelial NO synthase and potentiated ERK1/2 phosphorylations. In conclusion, hypoadiponectinemia induces APPL1 downregulation in the resistance vessels, contributing to the development of vascular insulin resistance by differentially modulating the Akt/endothelial NO synthase/NO and ERK1/2/endothelin-1 pathways in vascular endothelium in normotensive ySHRs.

Topics: Adaptor Proteins, Signal Transducing; Adiponectin; Animals; Arterioles; Cells, Cultured; Disease Models, Animal; Down-Regulation; Endothelin-1; Humans; Hypertension; Insulin; Insulin Resistance; Male; MAP Kinase Signaling System; Metabolism, Inborn Errors; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Nitric Oxide; Nitric Oxide Synthase Type III; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Umbilical Veins; Vascular Resistance; Vasodilation