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Abstract Objective: To elucidate the effect of diabetes mellitus (DM) on the atherosclerotic process in saphenous vein grafts by determining urotensin-II (U-II) levels in harvested saphenous veins of patients who underwent coronary artery bypass grafting (CABG). Methods: Coronary artery disease (CAD) patients who underwent CABG were divided into two groups: Group I (eight non-diabetic patients; CAD group) and Group II (13 patients; DM+CAD group). All patients underwent coronary angiography prior to surgery and Gensini score was used to determine the severity of coronary atherosclerosis. Saphenous vein samples were stained with hematoxylin-eosin and U-II, then damage score, H-Score, and vein layer thicknesses were calculated and statistically evaluated. Results: In light microscopic evaluation, significant difference was observed between the groups in terms of endothelial cells damage, internal elastic lamina degradation, and tunica media vascular smooth muscle cells (VSMCs) damage (P<0.001). U-II immunoreactivity was increased in tunica adventitia in the DM+CAD group (P=0.002). The increase in foam cells was directly proportional to the thickening of the subendothelial layer, and this increased U-II immunoreactivity. Gensini score was higher in the DM+CAD group than in the CAD group (P=0.002). Conclusion: Our results show that saphenous vein grafts are already atherosclerotic before they are grafted in CAD patients. This disease is more severe in diabetic CAD patients and these changes can be detected using U-II immunoreactivity.
Subject(s)
Humans , Male , Female , Urotensins , Coronary Artery Disease/surgery , Coronary Artery Disease/diagnostic imaging , Saphenous Vein/diagnostic imaging , Coronary Artery Bypass , Endothelial CellsABSTRACT
Increased serum urotensin II (UII) levels in human cirrhotic populations have been recently shown, but the long-term effects of UII receptor antagonist on the cirrhosis have not been investigated. To investigate the therapeutic effects of urotensin II receptor (UT) antagonist palosuran on rats with carbon tetrachloride (CCl)-induced cirrhosis, the hepatic and systemic hemodynamics, liver fibrosis, the metalloproteinase-13 (MMP-13)/tissue inhibitor of metalloproteinase-1 (TIMP-1) ratio, hepatic Rho-kinase activity, and the endothelial nitric oxide synthase (eNOS) activity are measured in CCl-cirrhotic rats treated with palosuran or vehicle for 4 weeks. Primary hepatic stellate cells (HSCs) are used to investigate the changes in UII/UT expression and the in vitro effect of palosuran. Compared with the vehicle-treated cirrhotic rats, treatment with palosuran can reduce the portal pressure (PP), decrease the risk of liver fibrosis and the level of α smooth muscle actin, collagen-I (COL-I), and transforming growth factor β expression. However, treatment with palosuran can increase MMP-13/TIMP-1, pvasodilator-stimulated phosphoprotein (p-VASP), and p-eNOS expression. Moreover, in vitro UII/UT mRNA expression increases during HSC activation. MMP-13/TIMP-1, COL-I, and p-VASP are inhibited after palosuran treatment. Our data indicate that long-term administration of palosuran can decrease PP in cirrhosis, which results from decreased hepatic fibrosis and enhanced eNOS-dependent HSC vasodilatation.
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Objective: To investigate the effects of urantide on the expressions of type IV collagen (Col IV) in thoracic aorta and vascular smooth muscle cells (VSMC) in the rats with atherosclerosis (AS), and to clarify its mechanism of prevention and treatment of AS Methods: A total of 180 Wistar rats were randomly divided into normal control group (n=30) and AS model group (n=150). The rat models of AS were established by feeding on high-fat diet or intraperitoneally injecting vitamin Da (VDa). The AS model rats were randomly divided into AS group, fluvestation (Flu) group and urantide group (3, 7, and 14 d groups). The expression of Col IV in thoracic aorta wall of the rats was detected by immunohistochemistry. The levels of hydroxyproline (HYP) in serum and urine of the rats in various groups were measured by ELISA. The VSMC were randomly divided into normal control group, urotensin E (U II 10~smol • L_ 1) group, Flu group and urantide (10~10to 10~" mol • L_ 1) groups. The levels of Col IV in VSMC of the rats in various groups were determined by ELISA. Results: There was a significant difference in the expression levels of Col IV in the irregular plaques of the thoracic aorta of the rats between various groups (F = 3 5 . 0 9, P < 0 . 01). The expression levels of Col IV in thoracic aorta of the rats in AS group were significantly increased compared with normal control group (P < 0 . 01); the intensity and extent of Col IV positive staining in urantide group were lower than those in AS group (P < 0 . 01). There were significant differences in the serum and urine HYP levels between various groups (F = 2 4 . 38, P < 0 . 01; F=26. 72, P < 0 . 01). Compared with normal control group, the serum HYP level of the rats in AS group were significantly increased (P < 0 . 01), and the urine HYP level was significantly decreased (P < 0 . 01). Compared with AS group, the serum HYP levels in urantide groups were significantly decreased (P < 0 . 01) and the urine HYP levels were significantly increased (P < 0. 01), no less than the level in Flu group. The expression levels of Col IV in the culture supernatant of VSMC in the rats in various groups had significantly difference (F = 3 1 . 04, P < 0 . 01). The expression level of Col IV in the culture supernatant of VSMC of the rats in U II group was significantly increased compared with normal control group (P < 0 . 01); the expression levels of Col IV in the culture supernatant of VSMC of the rats in urantide groups were significantly decreased compared with U II group (P < 0 . 05 or P < 0 . 01). Conclusion: Urantide can inhibit the expressions of Col IV in the thoracic aorta and VSMC of the AS rats and alleviate the degree of AS lesions, which provides the experimental evidence for the clinical application of urantide in the treatment of AS.
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Objective: To investigate the effects of Urantide on the expressions of c-Jun N-terminal kinase (JNK) mRNA and protein in the thoracic aorta tissue of the rats with atherosclerosis (AS) • and to elucidate the molecular mechanism and significance of prevention and treatment of AS. Methods: The AS rat models were established by intraperitoneal injection of Vitamin D combined with high-fat diet and control group was set up at the same time. A total of 150 AS model rats were divided into model group, simvastatin group. IJrantide 3 d group. Urantide 7 d group and Urantide 14 d group ( n= 30). The rats in simvastatin group were adminstrated with simvastatin by gavage for 14 d. and the rats in Urantide groups were injected with Urantide by caudal vein for 3. 7. and 14 d. The serum markers of the rats in various groups were detected by automatic biochemical analyzer; the morphology of rat thoracic aorta tissue was observed by HE staining; the expression levels of JNK mRNA and protein in the rat thoracic aorta tissue were detected by immunohistochemical staining. qRT-PCR and Western blotting methods. Results: Compared with control group, the serum levels of triglyceride (TG). total cholesterol (TC) and low density lipoprotein (LDL) of the rats in model group were increased (P<0. 05). and the level of high-density lipoprotein (HDL) was decreased ( P<.0. 05). The HE staining results showed the formation of bubbling cells in the thoracic aorta tissue, rupture of medullary elastic fibers and calcification of the rats in model group; compared with model group, the pathological symptoms of the thoracic aorta tissue of the rats in simvastatin group and Urantide groups were improved. The immunohistochemistry results showed that the JNK positive particles were weakly expressed in the rat thoracic aorta tissue in control group; the expression intensity of JNK in the rat thoracic aorta tissue in model group was increased ( P<0. 05); compared with model group, the expression intensities of JNK in the rat thoracia aorta tissue in Urantide groups were significantly decreased (P∗C0. 05). The qRT-PCR and Western blotting results showed that the expression levels of JNK mRNA and protein in the rat thoracic aorta tissue in model group were significantly increased ( P
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Urotensin II (UII) is a mitogenic and hypertrophic agent that can induce the proliferation of vascular cells. UII inhibition has been considered as beneficial strategy for atherosclerosis and restenosis. However, currently there is no therapeutics clinically available for atherosclerosis or restenosis. In this study, we evaluated the effects of a newly synthesized UII receptor (UT) antagonist, KR-36996, on the proliferation of SMCs in vitro and neointima formation in vivo in comparison with GSK-1440115, a known potent UT antagonist. In primary human aortic SMCs (HASMCs), UII (50 nM) induced proliferation was significantly inhibited by KR-36996 at 1, 10, and 100 nM which showed greater potency (IC₅₀: 3.5 nM) than GSK-1440115 (IC₅₀: 82.3 nM). UII-induced proliferation of HASMC cells was inhibited by U0126, an ERK1/2 inhibitor, but not by SP600125 (inhibitor of JNK) or SB202190 (inhibitor of p38 MAPK). UII increased the phosphorylation level of ERK1/2. Such increase was significantly inhibited by KR-36996. UII-induced proliferation was also inhibited by trolox, a scavenger for reactive oxygen species (ROS). UII-induced ROS generation was also decreased by KR-36996 treatment. In a carotid artery ligation mouse model, intimal thickening was dramatically suppressed by oral treatment with KR-36996 (30 mg/kg) which showed better efficacy than GSK-1440115. These results suggest that KR-36996 is a better candidate than GSK-1440115 in preventing vascular proliferation in the pathogenesis of atherosclerosis and restenosis.
Subject(s)
Animals , Humans , Mice , Atherosclerosis , Carotid Arteries , In Vitro Techniques , Ligation , Muscle, Smooth , Muscle, Smooth, Vascular , Neointima , Phosphorylation , Reactive Oxygen SpeciesABSTRACT
Urotensin II (UII) is the most potent vasoconstrictor among the identified vasoactive peptides. UII and its receptor (UT), which play varies of physiological roles, are widely expressed in central nerve system and peripheral organs. The change on the expressional level of UII/UT system has been proved to be closely correlated with pathological conditions. Therefore, UII/UT system was considered to be a potential target for treating many diseases. This review article is devoted to the latest research progress of UII/UT system in several aspects including ligand and receptor distribution, physiological activity, characteristics under pathological conditions and antagonist classification.
ABSTRACT
Urotensin II (UII) is a potent vasoactive peptide and mitogenic agent to induce proliferation of various cells including vascular smooth muscle cells (VSMCs). In this study, we examined the effects of a novel UII receptor (UT) antagonist, KR-36676, on vasoconstriction of aorta and proliferation of aortic SMCs. In rat aorta, UII-induced vasoconstriction was significantly inhibited by KR-36676 in a concentration-dependent manner. In primary human aortic SMCs (hAoSMCs), UII-induced cell proliferation was significantly inhibited by KR-36676 in a concentration-dependent manner. In addition, KR-36676 decreased UII-induced phosphorylation of ERK, and UII-induced cell proliferation was also significantly inhibited by a known ERK inhibitor U0126. In mouse carotid ligation model, intimal thickening of carotid artery was dramatically suppressed by oral treatment with KR-36676 (30 mg/ kg/day) for 4 weeks compared to vehicle-treated group. From these results, it is indicated that KR-36676 suppress UII-induced proliferation of VSMCs at least partially through inhibition of ERK activation, and that it also attenuates UII-induced vasoconstriction and vascular neointima formation. Our study suggest that KR-36676 may be an attractive candidate for the pharmacological management of vascular dysfunction.
Subject(s)
Animals , Humans , Mice , Rats , Aorta , Carotid Arteries , Cell Proliferation , Ligation , Muscle, Smooth , Muscle, Smooth, Vascular , Neointima , Phosphorylation , VasoconstrictionABSTRACT
Objective: To observe the relationship between the dynamic changes of plasma levels of urotensin II (UII) and the stability of coronary atherosclerotic plaque in patients with acute coronary syndrome (ACS). Methods: Our research included 2 groups: ACS group,n=135 consecutive patients treated in our hospital from 2013-03 to 2013-08 that including unstable angina pectoris (UAP) sub-group,n=7, non-ST segment elevation myocardial infarction (NSTEMI) sub-group,n=22 and STEMI sub-group,n=106. In addition, there was a Control group,n=48 healthy subjects. Plasma levels of UII, hs-CRP and NT-proBNP were examined and compared among different groups at different time points. Results: Compared with Control group at immediate admission, ACS group had increased plasma level of UII (39.82 ± 22.28) pg/ml vs (26.88 ± 6.09) pg/ml,P Conclusion: Plasma levels of UII have been changing in different type of ACS patients at immediate admission, UII presented decreasing trend from UAP to NSTEMI to STEMI, while it had increasing trend upon stabilized condition; the admission level of UII had no correlation to inflammatory marker hs-CRP and ventricular overload marker NT-proBNP. UII is not only related to the extent of atherosclerosis, but also related to the nature of atherosclerosis or the stability of plaques.
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In this study, we investigated the effects of a selective urotensin II (UII) receptor antagonist, SB-657510, on the inflammatory response induced by UII in human umbilical vein endothelial cells (EA.hy926) and human monocytes (U937). UII induced inflammatory activation of endothelial cells through expression of proinflammatory cytokines (IL-1beta and IL-6), adhesion molecules (VCAM-1), and tissue factor (TF), which facilitates the adhesion of monocytes to EA.hy926 cells. Treatment with SB-657510 significantly inhibited UII-induced expression of IL-1beta, IL-6, and VCAM-1 in EA.hy926 cells. Further, SB-657510 dramatically blocked the UII-induced increase in adhesion between U937 and EA.hy926 cells. In addition, SB-657510 remarkably reduced UII-induced expression of TF in EA.hy926 cells. Taken together, our results demonstrate that the UII antagonist SB-657510 decreases the progression of inflammation induced by UII in endothelial cells.
Subject(s)
Humans , Cytokines , Endothelial Cells , Human Umbilical Vein Endothelial Cells , Inflammation , Interleukin-6 , Monocytes , Thromboplastin , Vascular Cell Adhesion Molecule-1ABSTRACT
Human urotensin-II (hU-II) is one of the most potent vasoconstrictors in mammals, even more potent than endothelin. It has a wide range of vasoactive properties dependent on the anatomic site and the species studied. Although it is expressed mainly in the brain and spinal cord, it is also detected in other tissues, such as the kidney. It has been recognized for over 30 years, however only recently it has become a major focus of clinical researches. It has been suggested that U-II may have a possible autocrine/paracrine functions in kidney, and may be an important target molecule in studying renal pathophsiology. Previously, we investigated the level of U-II in children with minimal change nephrotic syndrome (MCNS), and to our knowledge there is no study about the possible role of U-II in other childhood glomerulonephritis. We firstly determined the expression of h U-II in kidneys of children with several glomerular diseases. In the lights of literature and our findings, this review describes mainly the possible role of U-II in children with renal diseases and summarizes what is known, and what must be known about the U-II
La urotensina II (U-II) humana es uno de los vasoconstrictores más fuertes en los mamíferos, es incluso más potente que la endotelina. Tiene un amplio espectro de propiedades vasoactivas según su localización anatómica y las especies estudiadas. Si bien se expresa fundamentalmente en el cerebro y en la médula espinal, también se la detecta en otros tejidos como el riñón. Aunque se la conoce desde hace más de 30 años, sólo recientemente se transformó en un objetivo principal de las investigaciones clínicas. Se sugirió que la U-II podría tener funciones autocrinas/paracrinas en el riñón y que podría ser una importante molécula blanco en el estudio de la fisiopatología renal. Con anterioridad investigamos el nivel de U-II en niños con síndrome nefrótico de cambios mínimos (SNCM) y según nuestro conocimiento no existe ningún estudio acerca del posible papel de la U-II en otras glomerulonefritis infantiles. En primer lugar determinamos la expresión de la U-II en riñones de niños con varias enfermedades glomerulares. En función de la literatura y de nuestros hallazgos, en esta revisión se describe esencialmente el posible papel de la U-II en niños con enfermedades renales y se resumen los conocimientos disponibles y lo que resta saber acerca de la U-II.