| 1. |
- Dimitrijevic, Ivan, et al.
(författare)
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Increased angiotensin II type 1 receptor expression in temporal arteries from patients with giant cell arteritis.
- 2009
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Ingår i: Ophthalmology. - : Elsevier BV. - 1549-4713 .- 0161-6420. ; 116:5, s. 990-996
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Currently, giant cell arteritis (GCA) is primarily treated with corticosteroids or immunomodulating agents, but there is interest in identifying other noncorticosteroid alternatives. Similarities exist in the injury pathways between GCA and atherosclerosis. Angiotensin II is a vasoactive peptide involved in vessel inflammation during atherosclerosis, and angiotensin II receptor inhibitors are effective in preventing atherosclerosis. The present study was performed to elucidate the role of angiotensin type 1 (AT(1)) and type 2 (AT(2)) receptors in GCA. DESIGN: Experimental retrospective immunohistochemical study of temporal arteries using archival formalin-fixed, paraffin-embedded tissue. PARTICIPANTS: Ten patients with GCA and 10 control patients, who were clinically suspected of having GCA but were diagnosed as not having GCA, were included. METHODS: Immunohistochemistry, using anti-AT(1) and anti-AT(2) antibodies, was performed on formalin-fixed and paraffin-embedded temporal arteries. MAIN OUTCOME MEASURES: AT(1) and AT(2) receptor immunostaining intensity was quantified. RESULTS: Hematoxylin-eosin-stained sections of temporal arteries from patients with GCA showed intimal hyperplasia, internal elastic lamina degeneration, and band-shaped infiltrates of inflammatory cells, including lymphocytes, histocytes, and multinucleated giant cells. AT(1) receptor staining was primarily observed in the medial layer of the temporal arteries and was higher in the patients with GCA than in the control patients. This was a result of increased AT(1) receptor immunostaining of both vascular smooth muscle cells and infiltrating inflammatory cells. Only faint immunostaining was seen for AT(2) receptors, primarily in the endothelial cells, and to a lesser extent on the smooth muscle cells. Immunostaining with antibodies for the AT(2) receptor was similar in the patients with GCA and in controls. CONCLUSIONS: These results suggest that AT(1) receptors play a role in the development of GCA. Inhibition of the angiotensin system may thus provide a noncorticosteroid alternative for the treatment of GCA. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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| 2. |
- Dimitrijevic, Ivan, et al.
(författare)
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Increased endothelin 1 type B receptors in nasal lesions of patients with granulomatosis with polyangiitis.
- 2013
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Ingår i: American Journal of Rhinology & Allergy. - : SAGE Publications. - 1945-8924 .- 1945-8932. ; 27:6, s. 444-450
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Tidskriftsartikel (refereegranskat)abstract
- Endothelin 1 (ET-1) is a locally produced vasoactive peptide with proinflammatory capabilities. Systemic levels of ET-1 seem elevated in granulomatosis with polyangiitis (GPA). The aim of this study was to examine the involvement of the endothelin system in patients with GPA using nasal mucosal biopsies.
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| 3. |
- Dimitrijevic, Ivan, et al.
(författare)
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Increased expression of endothelin ETB and angiotensin AT(1) receptors in peripheral resistance arteries of patients with suspected acute coronary syndrome
- 2009
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Ingår i: Heart and Vessels. - : Springer Science and Business Media LLC. - 1615-2573 .- 0910-8327. ; 24:6, s. 393-398
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Tidskriftsartikel (refereegranskat)abstract
- Patients who experience chest pain, in which ischemic heart disease has been ruled out, still have an increased risk of future ischemic cardiac events and premature death, possibly due to subclinical endothelial dysfunction. A feature of endothelial dysfunction is an increased expression of arterial vasoconstrictor endothelin (ET) and angiotensin (AT) receptors. Our aim was to investigate if the arterial expressions of these receptors are changed in patients with suspected but ruled out acute coronary syndrome (ACS). Small subcutaneous arteries (diameter of 100 A mu m) were surgically removed in an abdominal biopsy from 12 patients suspicious of ACS (susp ACS), admitted to the medical telemetry unit for chest pain. The vessels were analyzed for their receptor protein expression by quantitative immunohistochemistry using specific antibodies directed against ETA, ETB, AT(1), and AT(2) receptors. The control group (controls) consisted of eight healthy volunteers matched for age and sex with no previous cardiac illness or medication. The susp ACS group had an increased expression of ETB (by 94%) and AT(1) (by 34%) receptors in the smooth muscle cells of resistance arteries as compared to the control group. There were no significant differences in AT(2) and ETA receptor expression between the groups. The results indicate that the expression of arterial smooth muscle ETB and AT(1) receptors are increased in patients with suspected but ruled out ACS. These receptor changes could be important in the regulation of coronary tone and in the development of atherosclerosis, and may be related to increased cardiovascular risk.
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| 4. |
- Dimitrijevic, Ivan, et al.
(författare)
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Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease
- 2009
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Endothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor expression in subcutaneous arteries from patients with different degrees of ischemic heart disease. Methods: Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A ( ETA) and type B (ETB), and angiotensin type 1 (AT(1)) and type 2 (AT(2)) receptors expression and function were examined using immunohistochemistry, Western blot and in vitro pharmacology. Results: ETA and, to a lesser extent, ETB receptor staining was observed in the healthy vascular smooth muscle cells. The level of ETB receptor expression was higher in patients undergoing CABG surgery (250% +/- 23%; P < 0.05) and in the patients with angina pectoris (199% +/- 6%; P < 0.05), than in the healthy controls (100% +/- 28%). The data was confirmed by Western blotting. Arteries from CABG patients showed increased vasoconstriction upon administration of the selective ETB receptor agonist sarafotoxin S6c, compared to healthy controls (P < 0.05). No such difference was found for the ETA receptors. AT(1) and, to a lesser extent, AT(2) receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT(1) receptor expression was higher in both the angina pectoris (128% +/- 25%; P < 0.05) and in the CABG patients (203% +/- 41%; P < 0.05), as compared to the healthy controls (100% +/- 25%). The increased AT(1) receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s). Conclusion: The results demonstrate, for the first time, upregulation of ETB and AT(1) receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.
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| 5. |
- Dimitrijevic, Ivan, et al.
(författare)
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Increased Tissue Endothelin-1 and Endothelin-B Receptor Expression in Temporal Arteries from Patients with Giant Cell Arteritis.
- 2010
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Ingår i: Ophthalmology. - : Elsevier BV. - 1549-4713 .- 0161-6420. ; 117, s. 628-636
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Endothelin (ET)-1 has been implicated in the atherosclerotic process and during inflammation. Similarity in the development process of giant cell arteritis (GCA) and atherosclerosis exists. Several ET receptor antagonists have been developed, principally to target cardiovascular disease states. High doses of corticosteroids currently are used in the treatment of GCA, whereas other treatments are not as reliably effective. The present study was performed to elucidate the role for ET-1, ET(A), and ET(B) receptors in GCA. DESIGN: Experimental, retrospective immunohistochemical study of temporal arteries using archival formalin-fixed, paraffin-embedded tissue. PARTICIPANTS: The study included 10 patients with GCA and 10 control patients with clinically suspected GCA but diagnosed not to have GCA. METHODS: Immunohistochemistry, with anti ET-1, anti-ET(A), and anti-ET(B) antibodies, was performed on formalin-fixed and paraffin-embedded temporal arteries. MAIN OUTCOME MEASURES: Endothelin-1, ET(A), and ET(B) receptor immunostaining intensities were quantified. RESULTS: Temporal arteries from the patients with GCA showed the typical histologic features, including intimal thickening, disruption or loss of the elastic lamina, and inflammatory infiltrates of lymphocytes, macrophages, and multinucleated giant cells. These features were associated with increased ET-1 and ET(B) receptor immunoreactivity in the medial layer of the temporal arteries and endothelial cells in patients with GCA compared with the controls. The increased ET-1 and ET(B) receptor immunoreactivity occurred in vascular smooth muscle cells (SMCs) and multinucleated giant cells. The ET-1 and ET(B) receptor immunoreactivity correlated with the degree of systemic inflammation. No changes were observed in ET(A) receptor expression in SMCs or endothelial cells compared with controls. CONCLUSIONS: The results suggest a role for ET-1 and ET(B) receptors in GCA. Inhibiting the ET system may provide a corticosteroid-sparing alternative in the treatment of GCA. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.
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| 6. |
- Dimitrijevic, Ivan, et al.
(författare)
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Reduced expression of angiotensin II and angiotensin receptor type 1 and type 2 in resistance arteries from nasal lesions in granulomatosis with polyangiitis (Wegener's granulomatosis).
- 2011
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Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 40, s. 448-452
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Angiotensin II (ANGII) is involved in vessel inflammation and is important in the development of cardiovascular disorders such as atherosclerosis. During active disease, patients with granulomatosis with polyangiitis (GPA; Wegener's granulomatosis) have accelerated atherosclerosis and ANGII inhibitors are recommended to these patients to reduce atherosclerosis. We assessed the hypothesis that the expression of ANGII and its receptors in arteries in granulomatous lesions change in GPA. Methods: ANGII and angiotensin receptors were quantified in vessels from granulomatous lesions from patients with GPA using immunohistochemistry. Anti- ANGI type 1 (AT1) and type 2 (AT2) antibodies were applied on formalin-fixed and paraffin-embedded biopsies from nasal mucous membranes from eight patients with GPA and eight controls. Results: ANGII expression was localized to the endothelial cells (ECs) in arteries and sparsely to vascular smooth muscle cells (VSMCs) in nasal biopsies. AT1 receptor (AT1R) staining was intense and located in the VSMCs in the medial layer of the control arteries. AT2 receptor (AT2R) immunostaining was faint and was located only in the ECs. Patients with GPA showed marked down-regulation of positively immunostained ECs for ANGII or AT2R, and a reduced number of AT1R in VSMCs. ANGII, AT1R, and AT2R staining was persistent on infiltrating leucocytes. Conclusions: These results suggest down-regulation of the angiotensin system in arteries in granulomatous nasal lesions in GPA. Inhibition of the angiotensin system may prove less efficient in inhibiting the vascular inflammation process in GPA.
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| 7. |
- Dimitrijevic, Ivan, et al.
(författare)
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The adhesion receptor CD-31 can be primed to rapidly adjust the neutrophil cytoskeleton.
- 2002
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 292:4, s. 1092-1097
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Tidskriftsartikel (refereegranskat)abstract
- The adhesion receptor CD-31 is expressed on neutrophils and endothelial cells and participates in transendothelial migration of neutrophils. Although necessary, information on CD-31-induced signaling and its influence on the shape-forming actin network is scarce. Here, we found that antibody engagement of CD-31 on suspended neutrophils triggered a prompt intracellular Ca(2+) signal, providing the cells had been primed with a chemotactic factor. Inhibition of Src-tyrosine kinases blocked this Ca(2+) signal, but not a fMet-Leu-Phe-induced Ca(2+) signal. Despite the ability of fMet-Leu-Phe to activate Src-tyrosine kinases, it did not per se induce tyrosine phosphorylation of CD-31. However, fMet-Leu-Phe did enable such a phosphorylation following an antibody-induced engagement of CD-31. This clustering also triggered a Ca(2+)-dependent depolymerization of actin and, surprisingly enough, a simultaneous polymerization. The ability of CD-31 to signal dynamic alterations in the cytoskeleton, particularly the Ca(2+)-induced actin depolymerization, further explains how neutrophils can squeeze themselves out between adjacent endothelial cells.
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| 8. |
- Dimitrijevic, Ivan
(författare)
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Vascular Endothelin and Angiotensin Receptors Regulation in Inflammatory Arterial Disorders
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present thesis is aimed to examine the hypothesis that the degree of vascular inflammation correlates with the expression of vascular endothelin and angiotensin receptors. The receptor changes were studied in subcutaneous resistance arteries in patients with different degrees of ischemic heart disease (IHD). In addition, patients with giant cell arteritis (GCA) were also investigated because of the massive inflammatory activity in affected vessels. For functional studies of the resistance arteries, sensitive myographs were used. Receptor protein levels were measured quantitatively using immunohistochemistry or western blot. Main results: 1. Patients with suspected acute coronary syndrome (angina pectoris) have increased expression of AT1 and ETB receptors in vascular smooth muscle cells (VSMC) in subcutaneous resistance arteries. 2. The level of the up-regulation of contractile AT1 and ETB receptors depends on the degree of underlying IHD. The phenomenon is also correlated to the level of the systolic blood pressure. 3. Temporal arteries from patients with GCA have up-regulation of AT1 and ETB receptors in the VSMC in the medial layer of the arterial wall. The degrees of up-regulation of ETB receptors are directly correlated to the degree of the systemic inflammatory response (CRP). 4. Accompanying lymphocytic infiltrates as well as giant cells in the lesions of the temporal arteries express high immunostaining of endothelin-1 and up-regulation of ETB and AT1 receptors as well. 5. De novo expression of tissue endothelin-1 was observed in the VSMC in the medial layer as well in the neointima in affected arteries. 6. ETB receptors mediate contraction of subcutaneous resistance arteries in ischemic heart disease. The present thesis demonstrated that there is increased ETB and AT1 receptor expression in VSMC in ischemic heart disease and in GCA which correlates with the degree of inflammation.
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