Leptin Induces Endothelin-1 in Endothelial Cells In Vitro

Abstract

Abstract-Leptin, a protein encoded by the obese gene, is produced by adipocytes and released into the bloodstream. In obese humans, serum leptin levels are increased and correlate with the individual's body mass index and blood pressure. Elevated serum concentrations of endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, were also observed in obese subjects. The pathomechanisms underlying this ET-1 increase in obesity are poorly understood. In the present study, we investigated the influence of the ob gene product leptin on the expression of ET-1 in human umbilical vein endothelial cells (HUVECs). Binding studies using 125 I-radiolabeled leptin revealed high-and low-affinity leptin binding sites on HUVECs (Kd1ϭ13.1Ϯ3.1 nmol/L and Kd2ϭ1390Ϯ198 nmol/L, respectively), mediating a time-and dose-dependent increase of ET-1 mRNA expression and protein secretion after incubation of HUVECs with leptin. This leptin-induced ET-1 expression was inhibited by preincubation of HUVECs with 0.75 mol/L antisense phosphorothioate oligonucleotides directed against the leptin receptor Ob-Rb. Furthermore, after incubation with leptin, increased nuclear staining of c-fos and c-jun, the major components of the transcription factor AP-1, and increased AP-1 DNA binding were observed. Transient transfection studies with ET-1 promoter constructs showed that leptin-induced promoter activity was abolished in the absence of AP-1 binding sites or by cotransfection with a plasmid overexpressing a mutated jun, which is able to bind c-fos but not DNA. Thus, leptin upregulates ET-1 production in HUVECs via a mechanism potentially involving jun binding members of the bZIP family. Key Words: endothelin Ⅲ obesity Ⅲ hypertension Ⅲ vasculature A lthough the association of obesity and hypertension is well established, 1 there is, however, scarce information about the underlying pathomechanisms. Recently, the adipocyte gained more attention, serving not only as a passive energy storage pool but also as an important source of endocrine-active peptides, thus leading to a novel concept of adipocyte function.One of the adipocyte-derived peptides involved in the control of body weight is the recently identified hormone leptin, 2 a protein encoded by the obese (ob) gene modulating lipid metabolism, 3 hematopoiesis, 4 pancreatic ␤-cell function, 5 and angiogenesis. 6,7 Mutation of the ob gene causes severe obesity in ob/ob mice, which can be reversed through administration of exogenous leptin. 8 -10 In contrast, serum leptin levels in obese humans are increased and correlate with their body mass index, 11 suggesting that obese subjects are resistant to endogenous leptin.Several alternate spliced isoforms of the leptin receptor (Ob-R) have been cloned (reviewed in Tartaglia 12 ) containing a single transmembrane domain and an extracellular domain homologous to the class I cytokine receptor family, but differing in the length of their cytoplasmic tail. The receptor with the full-length cytoplasmic domain (Ob-Rb, 302 amino acids) is predominantly expressed...

Leptin Induces Hypertrophy via Endothelin-1–Reactive Oxygen Species Pathway in Cultured Neonatal Rat Cardiomyocytes

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Leptin and hyperleptinemia - from friend to foe for cardiovascular function

“…Leptin elicits an NOdependent arterial vascular relaxation with the chloride ion being an important regulator in leptin-induced endothelial NO release (Kimura et al 2000). Leptin has been shown to stimulate endothelial NO synthesis, upregulate ET-1 production and promote accumulation of ROS in human umbilical vein endothelial cells (Bouloumie et al 1999, Lembo et al 2000, Yamagishi et al 2001, Quehenberger et al 2002, Vecchione et al 2002. The leptin-induced vascular NO production was further proven to be mediated through PI-3 kinase-independent endothelial nitric oxide synthase (eNOS) phosphorylation by the Akt pathway (Vecchione et al 2002).…”

Carotid cross-sectional wall area is significantly associated with serum leptin levels, independent of body mass index: the SABPA study

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