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Nesfatin-1 suppresses peripheral arterial remodeling without elevating blood pressure in mice.

ABSTRACT: Nesfatin-1 is a novel anorexic peptide hormone that also exerts cardiovascular protective effects in rodent models. However, nesfatin-1 treatment at high doses also exerts vasopressor effects, which potentially limits its therapeutic application. Here, we evaluated the vasoprotective and vasopressor effects of nesfatin-1 at different doses in mouse models. Wild-type mice and those with the transgene nucleobindin-2, a precursor of nesfatin-1, were employed. Wild-type mice were randomly assigned to treatment with vehicle or nesfatin-1 at 0.2, 2.0 or 10 μg/kg/day (Nes-0.2, Nes-2, Nes-10, respectively). Subsequently, mice underwent femoral artery wire injury to induce arterial remodeling. After 4 weeks, injured arteries were collected for morphometric analysis. Compared with vehicle, nesfatin-1 treatments at 2.0 and 10 μg/kg/day decreased body weights and elevated plasma nesfatin-1 levels with no changes in systolic blood pressure. Furthermore, these treatments reduced neointimal hyperplasia without inducing undesirable remodeling in injured arteries. However, nesfatin-1 treatment at 0.2 μg/kg/day was insufficient to elevate plasma nesfatin-1 levels and showed no vascular effects. In nucleobindin-2-transgenic mice, blood pressure was slightly higher but neointimal area was lower than those observed in littermate controls. In cultured human vascular endothelial cells, nesfatin-1 concentration-dependently increased nitric oxide production. Additionally, nesfatin-1 increased AMP-activated protein kinase phosphorylation, which was abolished by inhibiting liver kinase B1. We thus demonstrated that nesfatin-1 treatment at appropriate doses suppressed arterial remodeling without affecting blood pressure. Our findings indicate that nesfatin-1 can be a therapeutic target for improved treatment of peripheral artery disease.

SUBMITTER: Mori Y

PROVIDER: S-EPMC6499920 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesTo determine the subgroup specific associations between usual blood pressure and risk of peripheral arterial disease, and to examine the relation between peripheral arterial disease and a range of other types of vascular disease in a large contemporary cohort.DesignCohort study.SettingLinked electronic health records from 1990 to 2013 in the United Kingdom.Participants4,222,459 people aged 30-90 years, registered at a primary care practice for at least one year and with a blood pressure measurement.Main outcome measuresTime to first diagnosis of new onset peripheral arterial disease and time to first diagnosis of 12 different vascular events.ResultsA 20 mm Hg higher than usual systolic blood pressure was associated with a 63% higher risk of peripheral arterial disease (hazard ratio 1.63, 95% confidence interval 1.59 to 1.66). The strength of the association declined with increasing age and body mass index (P<0.001 for interaction) but was not modified by sex or smoking status. Peripheral arterial disease was associated with an increased risk of 11 different vascular events, including ischaemic heart disease (1.68, 1.58 to 1.79), heart failure (1.63, 1.52 to 1.75), aortic aneurysm (2.10, 1.79 to 2.45), and chronic kidney disease (1.31, 1.25 to 1.38), but not haemorrhagic stroke. The most common initial vascular event among those with peripheral arterial disease was chronic kidney disease (24.4% of initial events), followed by ischaemic heart disease (18.5% of initial events), heart failure (14.7%), and atrial fibrillation (13.2%). Overall estimates from this cohort were consistent with those derived from traditional studies when we pooled the findings in two meta-analyses.ConclusionsRaised blood pressure is a strong risk factor for peripheral arterial disease in a range of patient subgroups. Furthermore, clinicians should be aware that those with established peripheral arterial disease are at an increased risk of a range of other vascular events, including chronic kidney disease, ischaemic heart disease, heart failure, atrial fibrillation, and stroke.

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Nesfatin-1 suppresses peripheral arterial remodeling without elevating blood pressure in mice.

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