Deficiency in Melanocortin 1 Receptor Signaling Predisposes to Vascular Endothelial Dysfunction and Increased Arterial Stiffness in Mice and Humans

Rinne, Petteri; Ahola‐Olli, Ari; Nuutinen, Salla; Koskinen, Emilia; Kaipio, Katja; Eerola, Kim; Juonala, Markus; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T.; Savontaus, Eriika

doi:10.1161/atvbaha.114.305064

Cited by 23 publications

(21 citation statements)

References 28 publications

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“…In the aorta of recessive yellow mice deficient in MC1 signalling, contractile capacity and NO‐dependent relaxations are impaired and arterial stiffness is increased (Rinne et al . ). In addition, humans with weak MC1 function exhibit reduced flow‐mediated dilatations and increased arterial stiffness (Rinne et al .…”

Section: Nitric Oxidementioning

confidence: 97%

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Endothelial dysfunction and vascular disease - a 30th anniversary update

Vanhoutte¹,

et al. 2016

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The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best-characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDH-mediated responses). As regards the latter, hydrogen peroxide (H O ) now appears to play a dominant role. Endothelium-dependent relaxations involve both pertussis toxin-sensitive G (e.g. responses to α -adrenergic agonists, serotonin, and thrombin) and pertussis toxin-insensitive G (e.g. adenosine diphosphate and bradykinin) coupling proteins. New stimulators (e.g. insulin, adiponectin) of the release of EDRFs have emerged. In recent years, evidence has also accumulated, confirming that the release of NO by the endothelial cell can chronically be upregulated (e.g. by oestrogens, exercise and dietary factors) and downregulated (e.g. oxidative stress, smoking, pollution and oxidized low-density lipoproteins) and that it is reduced with ageing and in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and EDH, in particular those due to H O ), endothelial cells also can evoke contraction of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factors. Recent evidence confirms that most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells and that prostacyclin plays a key role in such responses. Endothelium-dependent contractions are exacerbated when the production of nitric oxide is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive and diabetic patients. In addition, recent data confirm that the release of endothelin-1 can contribute to endothelial dysfunction and that the peptide appears to be an important contributor to vascular dysfunction. Finally, it has become clear that nitric oxide itself, under certain conditions (e.g. hypoxia), can cause biased activation of soluble guanylyl cyclase leading to the production of cyclic inosine monophosphate (cIMP) rather than cGMP and hence causes contraction rather than relaxation of the underlying vascular smooth muscle.

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Section: Nitric Oxidementioning

confidence: 97%

“…In addition, humans with weak MC1 function exhibit reduced flow‐mediated dilatations and increased arterial stiffness (Rinne et al . ). These observations suggest a chronic physiological endothelial protective role of the hormone.…”

Section: Nitric Oxidementioning

confidence: 97%

Endothelial dysfunction and vascular disease - a 30th anniversary update

Vanhoutte¹,

et al. 2016

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“…Several previous studies showed that the melanocortin system mediates inflammation and plays a role in sepsis. In an in vivo study, mice with defective MC1R signaling had more severe vascular dysfunction in response to lipopolysaccharide (LPS) than did wild-type mice(23). In another study, mice treated with α-MSH had less liver damage in response to LPS compared to untreated mice, an effect that was mediated by decreased leukocyte infiltration and cytokine accumulation(24).…”

Section: Discussionmentioning

confidence: 99%

Melanocortin-1 Receptor Polymorphisms and the Risk of Complicated Sepsis After Trauma

Seaton

Parent

Sood

et al. 2017

Shock

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Objective To determine if melanocortin-1 receptor (MC1R) single nucleotide polymorphisms (SNPs) are associated with complicated sepsis after trauma. Background Nosocomial infections are an important cause of morbidity and mortality after trauma. Several SNPs in inflammation-related genes have been associated with sepsis. MC1R is an anti-inflammatory mediator that may be involved in the immune response after trauma. Methods We genotyped 8 common MC1R SNPs in genomic DNA from subjects enrolled in a previously reported prospective cohort study. Subjects were adult trauma patients admitted to the ICU at a Level I trauma center (2003–2005). Results A total of 1,246 subjects were included in the analysis. The majority were male (70%), severely injured (81%), and injured by a blunt mechanism (89%). Forty percent developed sepsis, and 23% developed complicated sepsis, which was defined as sepsis with organ dysfunction. In logistic regression analysis, with adjustments for age, sex, body mass index, injury severity score, red blood cell transfusion requirement, and mechanism of injury, the MC1RR163Q variant (rs885479) was associated with a lower risk of developing complicated sepsis (ORadj=0.48, 95%CI: 0.28–0.81, p=0.006). In a subgroup of 511 subjects with genome-wide SNP data, the association between the MC1RR163Q variant and complicated sepsis remained significant after adjusting for genetic substructure (by principal components) and the above clinical factors (ORadj=0.30, 95%CI: 0.13–0.70, p=0.005). Conclusions MC1RR163Q is associated with a lower risk of complicated sepsis after trauma. Therapeutic targeting of MC1R may be beneficial for trauma patients at risk for complicated sepsis.

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“…Recently, we and others showed that alpha-MSH and its analogue, melanotan 2, evoke anti-inflammatory and vasoactive effects both in endothelial cells and in a mouse model of atherosclerosis (Rinne et al 2014, Yang et al 2015. On the other hand, deficient MC1R function disturbs the vascular endothelial function both in mice and humans (Rinne et al 2015). The vasoprotective effects arise from the augmentation of nitric oxide availability (Davignon & Ganz 2004, Rinne et al 2013, whereas the alleviation of inflammation stems from the inhibition of nuclear factor kappa B-driven inflammation (Manna & Aggarwal 1998, Yang et al 2015.…”

Section: Introductionmentioning

confidence: 99%

Melanocortin overexpression limits diet-induced inflammation and atherosclerosis in LDLR−/− mice

Nuutinen

Ailanen

Savontaus

et al. 2018

Journal of Endocrinology

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Atherosclerosis is a chronic inflammatory disease of the arteries. The disease is initiated by endothelial dysfunction that allows the transport of leukocytes and low-density lipoprotein into the vessel wall forming atherosclerotic plaques. The melanocortin system is an endogenous peptide system that regulates, for example, energy homeostasis and cardiovascular function. Melanocortin treatment with endogenous or synthetic melanocortin peptides reduces body weight, protects the endothelium and alleviates vascular inflammation, but the long-term effects of melanocortin system activation on atheroprogression remain largely unknown. In this study, we evaluated the effects of transgenic melanocortin overexpression in a mouse model of atherosclerosis. Low-density lipoprotein receptor-deficient mice overexpressing alpha- and gamma-MSH (MSH-OE) and their wild-type littermates were fed either a regular chow or Western-style diet for 16 weeks. During this time, their metabolic parameters were monitored. The aortae were collected for functional analysis, and the plaques in the aortic root and arch were characterised by histological and immunohistochemical stainings. The aortic expression of inflammatory mediators was determined by quantitative PCR. We found that transgenic MSH-OE improved glucose tolerance and limited atherosclerotic plaque formation particularly in Western diet-fed mice. In terms of aortic vasoreactivity, MSH-OE blunted alpha-adrenoceptor-mediated vasoconstriction and enhanced relaxation response to acetylcholine, indicating improved endothelial function. In addition, MSH-OE markedly attenuated Western diet-induced upregulation of proinflammatory cytokines (, and) that contribute to the pathogenesis of atherosclerosis. These results show that the activation of the melanocortin system improves glucose homeostasis and limits diet-induced vascular inflammation and atherosclerotic plaque formation.

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Deficiency in Melanocortin 1 Receptor Signaling Predisposes to Vascular Endothelial Dysfunction and Increased Arterial Stiffness in Mice and Humans

Cited by 23 publications

References 28 publications

Endothelial dysfunction and vascular disease - a 30th anniversary update

Endothelial dysfunction and vascular disease - a 30th anniversary update

Melanocortin-1 Receptor Polymorphisms and the Risk of Complicated Sepsis After Trauma

Melanocortin overexpression limits diet-induced inflammation and atherosclerosis in LDLR−/− mice

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