| 1. |
- 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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| 2. |
- Chen, Qingwen, et al.
(författare)
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Cigarette smoke extract promotes human vascular smooth muscle cell proliferation and survival through ERK1/2- and NF-κB-dependent pathways.
- 2010
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Ingår i: The Scientific World Journal. - : Hindawi Limited. - 2356-6140 .- 1537-744X. ; 10, s. 2139-2156
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Tidskriftsartikel (refereegranskat)abstract
- Tobacco use is one of the major risk factors of cardiovascular disease. The underlying molecular mechanisms that link cigarette smoke to cardiovascular disease remain unclear. The present study was designed to examine the effects of dimethyl sulfoxide (DMSO)-soluble smoke particles (DSPs) on human aortic smooth muscle cell (HASMC) cultures, and to explore the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and nuclear factor-kappaB (NF-κB) signal mechanisms involved. Serum-starved HASMCs were treated with DSPs for up to 48 h. DSPs promoted cell proliferation in a concentration-dependent manner from 0.05 to 0.2 μl/ml. Activation of ERK1/2 and NF-κB was seen after exposure to DSPs. This occurred in parallel with the increase in cell population, bromodeoxyuridine incorporation, and cyclinD1/cyclin-dependent kinase 4 expression. Blocking phosphorylation of ERK1/2 by MAPK inhibitors U0126 and PD98059, and inhibiting activation of NF-κB by IkappaB (IκB) kinase inhibitors wedelolactone or IMD-0354, abolished the DSP effects. However, either a p38 inhibitor (SB203580) or an inhibitor of lipopolysaccharide (polymyxin B), or nicotinic receptor blockers (mecamylamine and alpha-bungarotoxin), did not inhibit a DSP-induced increase in the cell population. DSPs increased the expression of intercellular adhesion molecule 1 and the release of interleukin-6 in HASMCs, both of which were inhibited by ERK1/2 or NF-κB pathway inhibitors. Furthermore, cell apoptosis and necrosis were found in serum-starved HASMCs. DSPs decreased cell death and increased B-cell leukemia/lymphoma 2 expression. Blocking phosphorylation of ERK1/2 or NF-κB attenuated DSP-induced cell death inhibition. Cigarette smoke particles stimulate HASMC proliferation and inhibit cell death. The intracellular signal mechanisms behind this involve activation of ERK1/2 and NF-κB pathways.
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| 3. |
- Maddahi, Aida, et al.
(författare)
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Blockade of the MEK/ERK pathway with a raf inhibitor prevents activation of pro-inflammatory mediators in cerebral arteries and reduction in cerebral blood flow after subarachnoid hemorrhage in a rat model.
- 2011
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; May 4, s. 144-154
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral ischemia that develops after subarachnoid hemorrhage (SAH) carries high morbidity and mortality. Inflammatory mediators are involved in the development of cerebral ischemia through activation of the mitogen-activated protein kinase pathway. We hypothesized that blockade of the MAPkinase/ERK (MEK)/extracellular signal-regulated kinase (ERK) pathway upstream with a specific raf inhibitor would prevent SAH-induced activation of the cerebrovascular inflammatory response. The raf inhibitor SB-386023-b was injected intracisternally in our rat model at 0, 6, or 12 hours after the SAH. After 48 hours, cerebral arteries were harvested, and iNOS, interleukin (IL)-6, IL-1beta, matrix metalloproteinase (MMP)-9, tissue inhibitors of metalloproteinase (TIMP)-1, and phosphorylated ERK1/2 were investigated by immunofluorescence, real-time polymerase chain reaction (PCR), and Western blot analysis. Cerebral blood flow (CBF) was measured using autoradiography. Protein levels of MMP-9, TIMP-1, iNOS, IL-6, and IL-1beta were increased after SAH, as were mRNA levels of IL-6, MMP-9, and TIMP-1. After SAH, pERK1/2 was increased, but CBF was reduced. Treatment with SB-386023-b at 0 or 6 hours after SAH normalized CBF and prevented SAH-induced upregulation of MMPs, pro-inflammatory cytokines, and pERK1/2 proteins. These results suggested that inhibition of MEK/ERK signal transduction by a specific raf inhibitor administered up to 6 hours after SAH normalized the expression of pro-inflammatory mediators and extracellular matrix-related genes.Journal of Cerebral Blood Flow & Metabolism advance online publication, 28 April 2010; doi:10.1038/jcbfm.2010.62.
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| 4. |
- Maddahi, Aida, et al.
(författare)
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Enhanced cerebrovascular expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 via the MEK/ERK pathway during cerebral ischemia in the rat.
- 2009
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Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 10:Jun 4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cerebral ischemia is usually characterized by a reduction in local blood flow and metabolism and by disruption of the blood-brain barrier in the infarct region. The formation of oedema and opening of the blood-brain barrier in stroke is associated with enhanced expression of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). RESULTS: Here, we found an infarct volume of 24.8 +/- 2% and a reduced neurological function after two hours of middle cerebral artery occlusion (MCAO), followed by 48 hours of recirculation in rat. Immunocytochemistry and confocal microscopy revealed enhanced expression of MMP-9, TIMP-1, and phosphorylated ERK1/2 in the smooth muscle cells of the ischemic MCA and associated intracerebral microvessels. The specific MEK1/2 inhibitor U0126, given intraperitoneal zero or 6 hours after the ischemic event, reduced the infarct volume significantly (11.8 +/- 2% and 14.6 +/- 3%, respectively; P < 0.05), improved neurological function, normalized expression of phosphorylated ERK1/2, and reduced expression of MMP-9 and TIMP-1 in the vessel walls. Administration of U0126 12 hours after MCAO did not alter the expression of MMP-9. Immunocytochemistry showed no overlap in expression between MMP-9/TIMP-1 and the astrocyte/glial cell marker GFAP in the vessel walls. CONCLUSION: These data are the first to show that the elevated vascular expression of MMP-9 and TIMP-1, associated with breakdown of the blood-brain barrier following focal ischemia, are transcriptionally regulated via the MEK/ERK pathway.
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| 5. |
- Xu, Cang-Bao, et al.
(författare)
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Cigarette Smoke Extracts Promote Vascular Smooth Muscle Cell Proliferation and Enhances Contractile Responses in the Vasculature and Airway.
- 2010
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7843 .- 1742-7835. ; 107, s. 940-948
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Tidskriftsartikel (refereegranskat)abstract
- Cigarette smoke exposure is a strong risk factor for cardiovascular and respiratory diseases. However, the knowledge about how cigarette smoke induces damage to vasculature and airway is limited. The present study was designed to examine the effects of cigarette smoke particles extracted by heptane (heptane-soluble smoke particles, HSP), by water (water-soluble smoke particles, WSP) and by DMSO (DMSO-soluble smoke particles, DSP), which represent lipophilic, hydrophilic and ambiphoteric constituents from the cigarette smoke, respectively. Human aortic smooth muscle cell (HASMC) proliferation was assessed in cell culture. Rat resistance artery and airway contractile responses to serotonin, U46619, phenylephrine, noradrenaline, acetylcholine, des-Arg(9)-bradykinin, bradykinin, sarafotoxin 6c and endothelin-1 were monitored by a sensitive myograph system. Immunocytochemistry and cell-based phosphoELISA assay were used to demonstrate activation of extracellular signal-regulated kinases 1/2 (ERK1/2). For the first time, our results demonstrate that although all the three extracts promote HASMC proliferation, the HSP and DSP effects occur earlier. HSP and DSP, but not WSP, increase the contractile responses to sarafotoxin 6c, U46619 or bradykinin in rat mesenteric artery and/or in bronchi. ERK1/2 is activated by HSP and DSP in HASMCs and inhibition of ERK1/2 abrogated the smoke extracts-induced HASMC proliferation, while blockage of nicotinic receptors had no effects, suggesting that the toxic effects of the smoke extracts occur via activation of intracellular ERK1/2 signalling, but not nicotinic receptors.
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