Abstract
Adipose tissue hormone leptin induces endothelium-dependent vasorelaxation mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHF). Previously it has been demonstrated that in short-term obesity the NO-dependent and the EDHF-dependent components of vascular effect of leptin are impaired and up-regulated, respectively. Herein we examined the mechanism of the EDHF-dependent vasodilatory effect of leptin and tested the hypothesis that alterations of acute vascular effects of leptin in obesity are accounted for by chronic hyperleptinemia. The study was performed in 5 groups of rats: (1) control, (2) treated with exogenous leptin for 1 week to induce hyperleptinemia, (3) obese, fed highly-palatable diet for 4 weeks, (4) obese treated with pegylated superactive rat leptin receptor antagonist (PEG-SRLA) for 1 week, (5) fed standard chow and treated with PEG-SRLA. Acute effect of leptin on isometric tension of mesenteric artery segments was measured ex vivo. Leptin relaxed phenylephrine-preconstricted vascular segments in NO- and EDHF-dependent manner. The NO-dependent component was impaired and the EDHF-dependent component was increased in the leptin-treated and obese groups and in the latter group both these effects were abolished by PEG-SRLA. The EDHF-dependent vasodilatory effect of leptin was blocked by either the inhibitor of cystathionine γ-lyase, propargylglycine, or a hydrogen sulfide (H2S) scavenger, bismuth (III) subsalicylate. The results indicate that NO deficiency is compensated by the up-regulation of EDHF in obese rats and both effects are accounted for by chronic hyperleptinemia. The EDHF-dependent component of leptin-induced vasorelaxation is mediated, at least partially, by H2S.
Highlights
Increased adiposity and obesity are the leading causes of arterial hypertension and atherosclerosis, the most prevalent cardiovascular diseases associated with endothelial dysfunction [1,2]
Conditions associated with chronic hyperleptinemia such as obesity, type 2 diabetes, chronic kidney disease, preeclampsia and obstructive sleep apnea are characterized by endothelial dysfunction and/or hypertension [14,15,16]
The in vitro activity of the both non-pegylated and pegylated superactive rat leptin antagonists (D23L/L39A/D40A/F41A) was similar to that of similar mutants of mouse, human [28] and ovine [22] indicating that the similarity of the effect of the D23L mutation in different species is likely related to the fact that the sequence of amino acids 6–28 (VQDDTKTLIKTIVTRINDISHTQ), making up the main part of the first a-helix, is identical in human, mouse, rat, ovine, bovine and pig leptins
Summary
Increased adiposity and obesity are the leading causes of arterial hypertension and atherosclerosis, the most prevalent cardiovascular diseases associated with endothelial dysfunction [1,2]. Under normal physiological conditions leptin has no acute effect on blood pressure because it activates both pressor (sympathetic nervous system, SNS) and depressor (vasodilation and natriuresis) mechanisms in the balanced manner. Conditions associated with chronic hyperleptinemia such as obesity, type 2 diabetes, chronic kidney disease, preeclampsia and obstructive sleep apnea are characterized by endothelial dysfunction and/or hypertension [14,15,16]. It is unclear if the enhancement of detrimental effects of leptin such as SNS and oxidative stress or reduced leptininduced vasorelaxation due to leptin resistance is more important in the pathogenesis of vascular dysfunction
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