Relaxin improves TNF-α-induced endothelial dysfunction: the role of glucocorticoid receptor and phosphatidylinositol 3-kinase signalling

Dschietzig, Thomas; Brecht, Anna; Bartsch, Cornelia; Baumann, Gert; Stangl, Karl; Alexiou, Konstantin

doi:10.1093/cvr/cvs149

Cited by 63 publications

(83 citation statements)

References 39 publications

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“…Chronic subcutaneous infusion and acute intravenous injection of Rln also selectively enhance bradykinin-mediated relaxation in rat mesenteric arteries (9,14). Similarly, aortic rings treated in vitro with TNF-␣ and coincubated with Rln also show improved ACh-mediated relaxation (5). Furthermore, acute in vivo Rln treatment (6.5 h) improves endothelial function in the aorta of chow-fed but not high-fat diet-fed mice (1).…”

Section: Unlike Resistance Arteries Endogenous Relaxin Has Very Littmentioning

confidence: 95%

“…Furthermore, acute in vivo Rln treatment (6.5 h) improves endothelial function in the aorta of chow-fed but not high-fat diet-fed mice (1). These vasorelaxant effects of Rln on arteries are not only mediated by NO via increased endothelial NO synthase (eNOS) phosphorylation and activity (5,14) and increased inducible NOS (iNOS) expression (14) but also involve intermediate-conductance Ca 2ϩ -activated K ϩ channeldependent endothelium-derived hyperpolarization and prostacyclin (PGI 2 ) in the mesenteric arteries (14). Thus, Rln may function through different vasodilatory pathways in conduit (i.e., aorta) versus resistance arteries (i.e., mesenteric artery).…”

Section: Unlike Resistance Arteries Endogenous Relaxin Has Very Littmentioning

confidence: 99%

“…Rln acts on its major receptor, Rln/insulin-like family peptide receptor 1 (RXFP1), which is differentially expressed in endothelial and vascular smooth muscle cells in different arteries, including the aorta (9). Based on evidence that Rln treatment is capable of stimulating vasodilation in the aorta (1,5) and endogenous Rln is produced by the aorta (17) and the fact that there are known functional differences between resistance and conduit arteries, we investigated vascular phenotypes attributed to Rln action on RXFP1 in the aorta and to what extent phenotypes in this artery are exacerbated by aging. We compared ACh and glyceryl trinitrate (GTN)-mediated relaxation and analyzed underlying vasodilatory pathways in the abdominal aorta of male Rln Ϫ/Ϫ and wild-type (Rln ϩ/ϩ ) mice at 4 and 16 mo of age.…”

Section: Unlike Resistance Arteries Endogenous Relaxin Has Very Littmentioning

confidence: 99%

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Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice

Jelinic

Parry

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Ng HH, Jelinic M, Parry LJ, Leo C. Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice. Am J Physiol Heart Circ Physiol 309: H285-H296, 2015. First published May 8, 2015 doi:10.1152/ajpheart.00786.2014.-The vascular effects of exogenous relaxin (Rln) treatment are well established and include decreased myogenic reactivity and enhanced relaxation responses to vasodilators in small resistance arteries. These vascular responses are reduced in older animals, suggesting that Rln is less effective in mediating arterial function with aging. The present study investigated the role of endogenous Rln in the aorta and the possibility that vascular dysfunction occurs more rapidly with aging in Rln-deficient (Rln Ϫ/Ϫ ) mice. We compared vascular function and underlying vasodilatory pathways in the aorta of male wild-type (Rln ϩ/ϩ ) and Rlnmice at 4 and 16 mo of age using wire myography. Superoxide production, but not nitrotyrosine or NADPH oxidase expression, was significantly increased in the aorta of young Rln Ϫ/Ϫ mice, whereas endothelial nitric oxide (NO) synthase and basal NO availability were both significantly decreased compared with Rln ϩ/ϩ mice. In the presence of the cyclooxygenase inhibitor indomethacin, sensitivity to ACh was significantly decreased in young Rln Ϫ/Ϫ mice, demonstrating altered NO-mediated relaxation that was normalized in the presence of a membrane-permeable SOD or ROS scavenger. These vascular phenotypes were not exacerbated in old Rln Ϫ/Ϫ mice and, in most cases, did not differ significantly from old Rln ϩ/ϩ mice. Despite the vascular phenotypes in Rln Ϫ/Ϫ mice, endothelium-dependent and -independent vasodilation were not adversely affected. Our data show a role for endogenous Rln in reducing superoxide production and maintaining NO availability in the aorta but also demonstrate that Rln deficiency does not compromise vascular function in this artery or exacerbate endothelial dysfunction associated with aging.

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Section: Unlike Resistance Arteries Endogenous Relaxin Has Very Littmentioning

confidence: 95%

Section: Unlike Resistance Arteries Endogenous Relaxin Has Very Littmentioning

confidence: 99%

Section: Unlike Resistance Arteries Endogenous Relaxin Has Very Littmentioning

confidence: 99%

See 1 more Smart Citation

Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice

Jelinic

Parry

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…Infiltration of visceral adipose tissue by macrophages is observed in conditions of pronounced hypertrophy in combination with increased secretion of proinflammatory cytokines, in particular TNF-a. TNF-a, in turn, is a potent inducer of the formation of interleukin-1 (IL-1), interleukin-6 (IL-6), C-reactive protein (CRP) and other compounds with the subsequent development of insulin resistance and a cascade of www.ah.viamedica.pl related metabolic disorders [65,76,78]. Adipocytes of the omentum and mesenteric area are characterized by high lipolytic ability, resulting in a massive flow of free fatty acids (FFA) and adipokines in the liver with the subsequent development of insulin resistance and dyslipidaemia.…”

Section: Nonspecific Systemic Inflammationmentioning

confidence: 99%

Arterial hypertension, obesity and non-alcoholic fatty liver disease: is there any connection?

Kuzmіnova

Gribenyuk

Osovska

et al. 2016

Arterial Hypertension

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The combination of hypertension, obesity and non-alcoholic fatty liver disease occurs in medical practice very often. A number of studies have shown that non-alcoholic fatty liver disease increases the risk of cardiovascular disease independently of other predictors and manifestations of the metabolic syndrome. Current issues of research and identification of common pathogenic relationships of obesity, hypertension, and liver steatosis are investigated in the article. According to the analysed literature, it is indicated that insulin resistance and compensatory hyperinsulinaemia are considered as one of the key factors in the development of this comorbidity. The processes of chronic inflammation are increasing with the growth of adipose tissue volume. Some researchers believe that non-specific systemic inflammation combines arterial hypertension, increased body weight (especially abdominal obesity), steatosis, dyslipidaemia, atherogenesis and arteriosclerosis into a single syndrome. The role of non-alcoholic fatty liver disease in the growth of the thickness of the intima-media complex was studied. It is known that adipose tissue functions as an endocrine organ, expresses genes encoding bioactive substances, and secretes certain cytokines. A strong link between dysfunction of adipose tissue in patients with non-alcoholic fatty liver disease and in such conditions as metabolic syndrome and cardiovascular disease was demonstrated. The dysfunction of the endothelium is also advisable to consider as the connecting link between liver disease, obesity and hypertension. Despite some understanding of common pathogenic mechanisms for the development of non-alcoholic fatty liver disease and hypertension, this comorbid pathology remains the subject of much debate and a variety of studies. key words: arterial hypertension, obesity, non-alcoholic fatty liver disease, insulin resistance, dyslipidaemia, non-specific systemic inflammation, endothelial dysfunction, atherogenesis.

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“…This working hypothesis is based on the following mainstays: ( i ) blood vessels are a physiological target of RLX and their cells express the specific RLX receptor RXFP1 25; ( ii ) RLX up‐regulates NOS expression and nitric oxide production in vascular endothelial cells 26, 27, 28, 29, 30; ( iii ) RLX improves inflammation‐induced endothelial dysfunction and NOS fall 31, 32; and ( iv ) RLX reduces oxidative stress and nitric oxide failure in different animal models of vascular injury 33, 34, 35, 36, 37.…”

Section: Introductionmentioning

confidence: 99%

Protection from cigarette smoke‐induced vascular injury by recombinant human relaxin‐2 (serelaxin)

Pini

Boccalini

Baccari

et al. 2016

J Cellular Molecular Medi

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Smoking is regarded as a major risk factor for the development of cardiovascular diseases (CVD). This study investigates whether serelaxin (RLX, recombinant human relaxin‐2) endowed with promising therapeutic properties in CVD, can be credited of a protective effect against cigarette smoke (CS)‐induced vascular damage and dysfunction. Guinea pigs exposed daily to CS for 8 weeks were treated with vehicle or RLX, delivered by osmotic pumps at daily doses of 1 or 10 μg. Controls were non‐smoking animals. Other studies were performed on primary guinea pig aortic endothelial (GPAE) cells, challenged with CS extracts (CSE) in the absence and presence of 100 ng/ml (17 nmol/l) RLX. In aortic specimens from CS‐exposed guinea pigs, both the contractile and the relaxant responses to phenylephrine and acetylcholine, respectively, were significantly reduced in amplitude and delayed, in keeping with the observed adverse remodelling of the aortic wall, endothelial injury and endothelial nitric oxide synthase (eNOS) down‐regulation. RLX at both doses maintained the aortic contractile and relaxant responses to a control‐like pattern and counteracted aortic wall remodelling and endothelial derangement. The experiments with GPAE cells showed that CSE significantly decreased cell viability and eNOS expression and promoted apoptosis by sparkling oxygen free radical‐related cytotoxicity, while RLX counterbalanced the adverse effects of CSE. These findings demonstrate that RLX is capable of counteracting CS‐mediated vascular damage and dysfunction by reducing oxidative stress, thus adding a tile to the growing mosaic of the beneficial effects of RLX in CVD.

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Relaxin improves TNF-α-induced endothelial dysfunction: the role of glucocorticoid receptor and phosphatidylinositol 3-kinase signalling

Cited by 63 publications

References 39 publications

Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice

Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice

Arterial hypertension, obesity and non-alcoholic fatty liver disease: is there any connection?

Protection from cigarette smoke‐induced vascular injury by recombinant human relaxin‐2 (serelaxin)

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