Abstract P183: Chemokine-like Receptor 1 Mediates the Vasoconstrictor Actions of Chemerin in vitro and in vivo

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Amanda Kennedy ◽  
Peiran Yang ◽  
Cai Read ◽  
Rhoda Kuc ◽  
Janet Maguire ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Therapeutic Potential ◽  
Plasma Concentrations ◽  
Resistance Arteries ◽  
Resistance Vessels ◽  
Increased Risk ◽  
First Time

Hypertensive patients have significantly higher plasma concentrations of the adipokine chemerin compared with healthy controls, and levels of chemerin positively correlate with systolic and diastolic blood pressure. Chemerin activates chemokine-like receptor 1 (CMKLR1 or ChemR23) but it also activates the ‘orphan’ G protein-coupled receptor 1 (GPR1) which has been linked with hypertension. It is therefore crucial to determine whether one or both of these receptors mediate the constrictor actions of chemerin in the vasculature in order to identify a potential new therapeutic target for the treatment of hypertension. Using immunohistochemistry and molecular biology, we localized chemerin to the endothelium, smooth muscle and adventitia, and CMKLR1 and GPR1 to the smooth muscle in human conduit and resistance vessels. Chemerin activated β-arrestin via heterologously expressed receptors GPR1 (pD 2 =9.30±0.05) and CMKLR1 (pD 2 =9.23±0.03) with comparable potency. CCX832, a small molecule antagonist, was fully characterized as highly selective for CMKLR1, with no effect on GPR1 in binding or cell-based functional assays. The C-terminal fragment of chemerin, C9 (chemerin149-157) contracted human saphenous vein (pD 2 =7.30±0.31) and resistance arteries (pD 2 =6.23±0.16), and caused a significant increase in blood pressure in rats in vivo (0.2 μmol, 9.1±1.0 mmHg). These actions were blocked by CCX832, confirming for the first time that a single chemerin receptor, CMKLR1, mediates the constrictor response in humans and in vivo. Our data suggest that chemerin activation of CMKLR1 may contribute to elevated blood pressure; this in combination with the known roles of chemerin in metabolic syndrome and diabetes, could lead to increased risk of cardiovascular disease. This study provides proof of principle that the therapeutic potential of selective CMKLR1 antagonists should be explored.

scholarly journals Dickkopf-1 Inhibition Reactivates Wnt/β-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo

2021 ◽  
Vol 22 (23) ◽  
pp. 12921
Author(s):  
Irina Giralt ◽  
Gabriel Gallo-Oller ◽  
Natalia Navarro ◽  
Patricia Zarzosa ◽  
Guillem Pons ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Positive Effects ◽  
Novel Therapeutic Strategies ◽  
And Function ◽  
Myogenic Markers ◽  
First Time ◽  
Dickkopf 1 ◽  
Proliferation And Invasion

The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to β-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression.

Effect of Propofol on Norepinephrine-induced Increases in [Ca2+](i) and Force in Smooth Muscle of the Rabbit Mesenteric Resistance Artery 

1998 ◽  
Vol 88 (6) ◽  
pp. 1566-1578 ◽  
Author(s):  
Nami Imura ◽  
Yoshihisa Shiraishi ◽  
Hirotada Katsuya ◽  
Takeo Itoh
Keyword(s):  
Smooth Muscle ◽  
Isometric Force ◽  
Resistance Artery ◽  
Resistance Arteries ◽  
High K ◽  
Small Resistance ◽  
Vasodilating Activity ◽  
Mesenteric Resistance Artery

Background Propofol (2,6-diisopropylphenol) possesses vasodilating activity in vivo and in vitro. The propofol-induced relaxation of agonist-induced contractions in small resistance arteries has not been clarified. Methods The effect of propofol was examined on the contractions induced by norepinephrine and high K+ in endothelium-denuded rabbit mesenteric resistance artery in vitro. The effects of propofol on the [Ca2+]i mobilization induced by norepinephrine and high K+ were studied by simultaneous measurement of [Ca2+]i using Fura 2 and isometric force in ryanodine-treated strips. Results Propofol attenuated the contractions induced by high K+ and norepinephrine, the effect being greater on the high K+-induced contraction than on the norepinephrine-induced contraction. In Ca2+-free solution, norepinephrine produced a transient contraction resulting from the release of Ca2+ from storage sites that propofol attenuated. In ryanodine-treated strips, propofol increased the resting [Ca2+]i but attenuated the increases in [Ca2+]i and force induced by both high K+ and norepinephrine. In the presence of nicardipine, propofol had no inhibitory action on the residual norepinephrine-induced [Ca2+]i increase, whereas it still modestly increased resting [Ca2+]i, as in the absence of nicardipine. Conclusions In smooth muscle of the rabbit mesenteric resistance artery, propofol attenuates norepinephrine-induced contractions due to an inhibition both of Ca2+ release and of Ca2+ influx through L-type Ca2+ channels. Propofol also increased resting [Ca2+]i, possibly as a result of an inhibition of [Ca2+]i removal mechanisms. These results may explain in part the variety of actions seen with propofol in various types of vascular smooth muscle.

The Bronchodilator Activity of AY-22093, a Prostanoic Acid Derivative

1974 ◽  
Vol 52 (1) ◽  
pp. 1-7 ◽  
Author(s):  
R. Greenberg ◽  
G. Beaulieu
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Guinea Pig ◽  
Acid Derivative ◽  
Prostaglandin E ◽  
Significant Protection ◽  
In Vitro Techniques ◽  
Bronchodilator Activity

The bronchodilator activities of AY-22093, prostaglandin E2 (PGE2), and isoproterenol were compared using in vivo and in vitro techniques. In the conscious guinea pig, an aerosol of AY-22093, PGE2, and isoproterenol afforded significant protection against histamine-induced bronchospasm; AY-22093 and isoproterenol were equally effective in protecting against antigen-induced anaphylaxis. In the anesthetized guinea pig, using the Konzett and Rössler technique, PGE2 (1 μg/kg, intravenously (i.v.)) inhibited the bronchoconstriction induced by histamine (10 μg/kg, i.v.) by 63% as compared with 37% inhibition after AY-22093 (1 μg/kg, i.v.). Larger intravenous doses of PGE2 and AY-22093 (10 and 20 μg/kg) caused almost complete inhibition of the histamine-induced bronchoconstriction. The administration of PGE2 (0.5–10 μg) or AY-22093 (5–100 μg) by aerosol inhibited the bronchoconstriction induced by histamine (10 μg/kg, i.v.) by 20–70%. Maximum bronchodilator effects occurred within 3 min and lasted for as long as 30 min after either route of administration. Both compounds caused a fall in blood pressure after intravenous but not after aerosol administration. AY-22093 relaxed the guinea pig tracheal strip where tone was induced by carbachol. This relaxation was not altered by propranolol. The results indicate that AY-22093 is a bronchodilator qualitatively similar to PGE2, having a direct effect on smooth muscle but less potent than PGE2.

scholarly journals Circadian Rhythmicity in Cerebral Microvascular Tone Influences Subarachnoid Hemorrhage–Induced Injury

Stroke ◽  
2021 ◽  
Author(s):  
Darcy Lidington ◽  
Hoyee Wan ◽  
Danny D. Dinh ◽  
Chloe Ng ◽  
Steffen-Sebastian Bolz
Keyword(s):  
Smooth Muscle ◽  
Subarachnoid Hemorrhage ◽  
Circadian Rhythms ◽  
Cerebral Arteries ◽  
Circadian Variation ◽  
Neurological Injury ◽  
Myogenic Tone ◽  
Resistance Arteries

Background and Purpose: Circadian rhythms influence the extent of brain injury following subarachnoid hemorrhage (SAH), but the mechanism is unknown. We hypothesized that cerebrovascular myogenic reactivity is rhythmic and explains the circadian variation in SAH-induced injury. Methods: SAH was modeled in mice with prechiasmatic blood injection. Inducible, smooth muscle cell–specific Bmal1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1) gene deletion (smooth muscle–specific Bmal1 1 knockout [sm-Bmal1 KO]) disrupted circadian rhythms within the cerebral microcirculation. Olfactory cerebral resistance arteries were functionally assessed by pressure myography in vitro; these functional assessments were related to polymerase chain reaction/Western blot data, brain histology (Fluoro-Jade/activated caspase-3), and neurobehavioral assessments (modified Garcia scores). Results: Cerebrovascular myogenic vasoconstriction is rhythmic, with a peak and trough at Zeitgeber times 23 and 11 (ZT23 and ZT11), respectively. Histological and neurobehavioral assessments demonstrate that higher injury levels occur when SAH is induced at ZT23, compared with ZT11. In sm-Bmal1 KO mice, myogenic reactivity is not rhythmic. Interestingly, myogenic tone is higher at ZT11 versus ZT23 in sm-Bmal1 KO mice; accordingly, SAH-induced injury in sm-Bmal1 KO mice is more severe when SAH is induced at ZT11 compared to ZT23. We examined several myogenic signaling components and found that CFTR (cystic fibrosis transmembrane conductance regulator) expression is rhythmic in cerebral arteries. Pharmacologically stabilizing CFTR expression in vivo (3 mg/kg lumacaftor for 2 days) eliminates the rhythmicity in myogenic reactivity and abolishes the circadian variation in SAH-induced neurological injury. Conclusions: Cerebrovascular myogenic reactivity is rhythmic. The level of myogenic tone at the time of SAH ictus is a key factor influencing the extent of injury. Circadian oscillations in cerebrovascular CFTR expression appear to underlie the cerebrovascular myogenic reactivity rhythm.

Epidemiologic and Genetic Associations of Erythropoietin With Blood Pressure, Hypertension, and Coronary Artery Disease

Hypertension ◽  
2021 ◽  
Vol 78 (5) ◽  
pp. 1555-1566
Author(s):  
Pengfei Sun ◽  
Nitin Kumar ◽  
Adrienne Tin ◽  
Jing Zhao ◽  
Michael R. Brown ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Coronary Artery Disease ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Odds Ratio ◽  
Genetic Associations ◽  
Artery Disease ◽  
Erythropoietin Level

While exogenous administration of recombinant erythropoietin has been associated with increased risk of hypertension, coronary artery disease, and mortality, it is not known if endogenous circulating erythropoietin level is associated with coronary artery disease and its risk factors. We measured and analyzed epidemiological and genetic associations of circulating plasma erythropoietin levels in 2 population cohorts, from China (N=4329) and the United States (N=3671). In vitro smooth muscle cell responses and in vivo murine studies of erythropoietin exposure were performed. Erythropoietin levels were positively and linearly associated with blood pressure traits and inversely associated with cholesterol levels and red cell indices. Higher erythropoietin level was associated with higher prevalence of hypertension (odds ratio, 1.20 [95% CI, 1.12–1.29], P =4.41×10 −7 ) and coronary artery disease (odds ratio, 1.16 [95% CI, 1.00–1.34], P =0.046). In a discovery stage genetic association study of erythropoietin level, we identified a previously reported locus on chromosome 6 (rs7776054 near HBS1L-MYB , P =4.86×10 −25 ) and a new locus on chromosome 4 (rs172629 near PDGFRA-KIT , P =2.1×10 −8 ), which was independently replicated. Meta-analysis of discovery and replication genetic association results identified a locus on chromosome 22 (rs855791 near TMPRSS6 , P =3.60×10 −9 ). Erythropoietin administration, within a physiological range of hematocrit achieved, induced hypertension in vivo and increased contraction of vascular smooth muscle cells in vitro. In conclusion, endogenous circulating erythropoietin level is influenced by common genetic variation and is associated with blood pressure traits, hypertension, and coronary artery disease. Vascular effects of erythropoietin demonstrated in vitro and in vivo support a newly discovered mechanism of hypertension and cardiovascular risk with potential implications for erythropoietic support in the clinic. Graphic Abstract: An online graphic abstract is available for this article.

Normoprolactinaemia in spontaneously hypertensive rats: absence of a close relationship between plasma concentrations of prolactin and systolic blood pressure

1990 ◽  
Vol 125 (3) ◽  
pp. 359-364 ◽  
Author(s):  
E. Aguilar ◽  
M. L. Rodríguez-Padilla ◽  
L. Pinilla
Keyword(s):  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Plasma Concentrations ◽  
Male Rats ◽  
Adult Males ◽  
Spontaneously Hypertensive ◽  
Close Relationship ◽  
Wistar Kyoto

ABSTRACT Prolactin has been involved in different types of hypertension both in man and in rats. In an attempt to substantiate this hypothesis, we have analysed the correlation between plasma concentrations of prolactin and systolic blood pressure (SBP) in female and male rats from spontaneously hypertensive (SH) and normotensive Wistar–Kyoto strains (30, 60 and 90 days old), as well as in adult female Wistar rats rendered hyperprolactinaemic by the administration of 100 μg testosterone propionate on day 1 of life, or adult males with low plasma concentrations of prolactin after administration of bromocriptine (4 mg/kg per day) over 15 days. Our results indicate a lack of correlation between plasma concentrations of prolactin and SBP since plasma concentrations of prolactin were normal in male and female SH rats and hyper- and hypoprolactinaemia did not affect SBP. In spite of these normal plasma concentrations of prolactin, SH rats showed subtle changes in the secretion of this hormone in vitro and in vivo in response to exogenous serotonin administration and to immobilization. Journal of Endocrinology (1990) 125, 359–364

P5506Proprotein convertase subtilisin/kexin 9 (PCSK9) and lipopolysaccharide (LPS) in patients with atrial fibrillation. A biomarker post-hoc analysis from the ATHERO-AF cohort

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
P Pignatelli Spinazzola ◽  
A Farcomeni ◽  
D Pastori ◽  
F Violi
Keyword(s):  
Atrial Fibrillation ◽  
Nadph Oxidase ◽  
Rank Test ◽  
Post Hoc Analysis ◽  
Increased Risk ◽  
Post Hoc ◽  
First Time ◽  
Nadph Oxidase Activation

Abstract Background Proprotein convertase subtilisin/kexin 9 (PCSK9) and lipopolysaccharides (LPS) are emerging as novel risk factors for cardiovascular events (CVEs). In vitro evidence suggested that PCSK9 production may be elicited by LPS via oxidative stress, However, their relationship in patients with atrial fibrillation (AF) has not been investigated. Methods Post-hoc analysis of a prospective, single centre cohort study of 907 patients with non-valvular AF. At baseline, PCSK9, LPS and NADPH oxidase (sNOX2-dp) were measured. We also assessed adherence to Mediterranean Diet (Med-Diet). PCSK9 and LPS were correlated to incidence of CVEs. Results At multivariate analysis, with PCSK9 above the median as dependent variable we found that high adherence to Med-Diet and antiplatelet drugs were inversely correlated to PCSK9 (odds ratio [OR] 0.737 95% Confidence interval [CI] 0.643–0.845 p=0.001 and OR 0.437 95% CI 0.219–0.871 p=0.017 respectively), while sNOX2-dp and LPS concentrations (OR 1.759 C.I. 95% 1.167–2.650, p=0.007 and OR 1.727 C.I. 95% 1.147–2.600 p=0.009 respectively) were directly correlated. In particular use of oil and wine were negatively associated to high PCSK9 levels (OR 0.376 95% CI 0.185–0.763, p=0.001 and OR 0.460 95% CI 0.289–0.733 p=0.007, respectively). Patients with concomitant high PCSK9 and LPS (highest tertile for both) had and increased risk of CVEs as compared to those with low levels (lowest tertile for both) with 48 and 29 CVEs in each group respectively (Log-Rank test, p=0.022) Conclusion This study demonstrated for the first time in vivo that circulating levels of PCSK9 are associated with high LPS concentration and NADPH oxidase activation. Concomitant increase of PCSK9 and LPS increased the risk of CVEs.

scholarly journals Prolyl 4-Hydroxylase Domain Protein 3-Inhibited Smooth-Muscle-Cell Dedifferentiation Improves Cardiac Perivascular Fibrosis Induced by Obstructive Sleep Apnea

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Jiayi Tong ◽  
Fu-chao Yu ◽  
Yang Li ◽  
Qin Wei ◽  
Chen Li ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Smooth Muscle ◽  
Sleep Apnea ◽  
Therapeutic Potential ◽  
Obstructive Sleep ◽  
Domain Protein ◽  
Cardiovascular Fibrosis

Background. Intermittent hypoxia (IH) induced by obstructive sleep apnea (OSA) is a leading factor affecting cardiovascular fibrosis. Under IH condition, smooth muscle cells (SMAs) respond by dedifferentiation, which is associated with vascular remodelling. The expression of prolyl 4-hydroxylase domain protein 3 (PHD3) increases under hypoxia. However, the role of PHD3 in OSA-induced SMA dedifferentiation and cardiovascular fibrosis remains uncertain. Methods. We explored the mechanism of cardiovascular remodelling in C57BL/6 mice exposed to IH for 3 months and investigated the mechanism of PHD3 in improving the remodelling in vivo and vitro. Results. In vivo remodelling showed that IH induced cardiovascular fibrosis via SMC dedifferentiation and that fibrosis improved when PHD3 was overexpressed. In vitro remodelling showed that IH induced SMA dedifferentiation, which secretes much collagen I. PHD3 overexpression in cultured SMCs reversed the dedifferentiation by degrading and inactivating HIF-1α. Conclusion. OSA-induced cardiovascular fibrosis was associated with SMC dedifferentiation, and PHD3 overexpression may benefit its prevention by reversing the dedifferentiation. Therefore, PHD3 overexpression has therapeutic potential in disease treatment.

Stretch-dependent (myogenic) tone in rabbit ear resistance arteries

1986 ◽  
Vol 250 (1) ◽  
pp. H87-H95 ◽  
Author(s):  
J. J. Hwa ◽  
J. A. Bevan
Keyword(s):  
Smooth Muscle ◽  
Vascular Tone ◽  
Mechanical Stretch ◽  
Myogenic Tone ◽  
Resistance Arteries ◽  
Physiological Regulation ◽  
Rabbit Ear ◽  
Arterial Tone

Rabbit ear resistance arteries are vessels with three to six layers of smooth muscle cells and an unstretched lumen diameter of 75-150 micron. Ring segments of these arteries, in response to mechanical stretch in vitro, developed a maintained tonic contraction. The stretch-dependent contraction achieved a plateau within 10-30 min. Smooth muscle relaxants, such as NaNO2 and papaverine, substitution of extracellular Ca2+ by subthreshold Ca2+ (25 microM), or exposure to the Ca2+ influx antagonist Mn2+ abolished the stretch-dependent tone. The extent of the tone was dependent on the level of the applied stretch and the extracellular Ca2+ concentration ( [Ca2+]o). The maximal tone developed at optimal stretch, and [Ca2+]o in the bath solution was 18.1 +/- 4.6% of the maximal contraction of the vessel to histamine. This level of tone is comparable to neurogenic tone developed in response to nerve stimulation within the physiological frequency range. The stretch-dependent tone is considered probably myogenic in origin, since it was present in arterial segments that had been chronically denervated by surgical sympathectomy, mechanically deprived of the endothelium, and multireceptor blocked (phenoxybenzamine, 10(-6) M). Our findings suggest first that the stretch-dependent tone is myogenic and may be similar to basal vascular tone arising from the stretch of arterial pressure and its changes in vivo. Second, the magnitude of myogenic tone is a function of the applied stretch and the [Ca2+]o. Finally, myogenic tone is important in the physiological regulation of arterial tone in the rabbit ear resistance arteries.

Studies in vivo and in vitro of terbutaline-induced β-adrenoceptor desensitization in healthy subjects

1987 ◽  
Vol 72 (1) ◽  
pp. 47-54 ◽  
Author(s):  
Arne Martinsson ◽  
Kjell Larsson ◽  
Paul Hjemdahl
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Cyclic Amp ◽  
Sympathetic Nerve ◽  
Healthy Subjects ◽  
Plasma Concentrations ◽  
Plasma Noradrenaline ◽  
Binding Studies

1. β-Adrenoceptor function was studied in eight healthy subjects before, during and 24 and 72 h after cessation of 2 weeks continuous oral treatment with the β2-adrenoceptor agonist terbutaline (sustained release, 7.5 mg twice daily). In vivo, blood pressure, heart rate, plasma noradrenaline and plasma cyclic AMP responses to isoprenaline (0.01, 0.02 and 0.05 μg min−1 kg−1 intravenously) were related to the plasma concentrations of isoprenaline. For comparison, β2-adrenoceptor function was evaluated in lymphocytes in vitro by studies of isoprenaline-induced accumulation of cyclic AMP and radioligand binding studies using 125I-iodohydroxybenzylpindolol. 2. In vivo, the β2-mediated plasma cyclic AMP response to isoprenaline was markedly attenuated during terbutaline treatment and was still reduced by 38% (P < 0.05) 72h. after discontinuation of treatment. The blood pressure and heart rate responses to isoprenaline were unaffected by treatment. Isoprenaline-induced elevations of plasma noradrenaline concentrations were markedly reduced during terbutaline treatment. This indicates an attenuation of isoprenaline-induced increases in sympathetic nerve function and could explain why no attenuation of the isoprenaline-induced vasodilatation was observed. Thus, plasma cyclic AMP seems to be a better marker than diastolic blood pressure when evaluating β2-adrenoceptor responsiveness in vivo in man, since it is not influenced by counter-regulatory increases in sympathetic nerve activity and/or noradrenaline overflow from sympathetic nerves. 3. In lymphocytes, the isoprenaline-stimulated cyclic AMP accumulation was reduced by 75% and the β-adrenoceptor binding sites were reduced by 40% 12 h after dosing. Also the lymphocyte β2-adrenoceptors recovered slowly after withdrawal of treatment. Normal responsiveness was not restored within 72 h after the last dose of terbutaline. 4. Thus, we obtained evidence in vivo and in vitro showing a markedly attenuated β2-adrenoceptor function, which persisted at least 72 h after discontinuation of terbutaline treatment. The slow rate of resensitization of β2-adrenoceptors after withdrawal may have practical implications in the treatment of, for example, asthma, since a state of ‘physiological β2-adrenoceptor blockade’ seems to be produced by β2-agonist treatment.

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