摘要:

Ror&agr; is an orphan nuclear receptor. In homozygous staggerer mutant mice (Rorasg/sg), a deletion within the Rora gene leads to an overexpression of inflammatory cytokines. Because inflammation and hypoxia are 2 key stimuli of ischemia-induced angiogenesis, we studied the role of Ror&agr; in this setting. Ischemia was induced by ligation of the right femoral artery in C57BL/6 Rora+/+and Rorasg/sgmice. After 3 and 28 days, angiogenesis was evaluated by microangiography, measurement of capillary density using immunohistochemistry (anti-CD31), and measurement of blood flow by laser Doppler imaging. At day 3, angiographic score and blood flow were similar in Rorasg/sgmice and in Rora+/+littermates. Conversely, at day 28, Rorasg/sgmice showed a significant 2-fold increase in angiographic score and a 3-fold increase in capillary density within the ischemic hindlimb compared with control. Functionally, this coincided with a significant rise in leg perfusion in Rorasg/sgmice (0.83±0.05 for ischemic/nonischemic leg perfusion ratio) compared with Ror+/+mice (0.66±0.04,P<0.05). In addition, more extensive angiogenesis in Rorasg/sgmice correlated with an increased expression of eNOS protein by 83±12% and 71±24% at 3 and 28 days, respectively (P<0.05), whereas the level of the antiangiogenic cytokine IL-12 was significantly reduced by 38±10% at day 28 (P<0.05). Conversely, no changes in VEGF expression were observed. Our study identifies for the first time a new role for Ror&agr; as a potent negative regulator of ischemia-induced angiogenesis.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Ventricular fibrillation (VF) is the leading cause of sudden cardiac death. Yet, the mechanisms of VF remain elusive. Pixel-by-pixel spectral analysis of optical signals was carried out in video imaging experiments using a potentiometric dye in the Langendorff-perfused guinea pig heart. Dominant frequencies (peak with maximal power) were distributed throughout the ventricles in clearly demarcated domains. The fastest domain (25 to 32 Hz) was always on the anterior left ventricular (LV) wall and was shown to result from persistent rotor activity. Intermittent block and breakage of wavefronts at specific locations in the periphery of such rotors were responsible for the domain organization. Patch-clamping of ventricular myocytes from the LV and the right ventricle (RV) demonstrated an LV-to-RV drop in the amplitude of the outward component of the background rectifier current (IB). Computer simulations suggested that rotor stability in LV resulted from relatively small rectification ofIB(presumablyIK1), whereas instability, termination, and wavebreaks in RV were a consequence of strong rectification. This study provides new evidence in the isolated guinea pig heart that a persistent high-frequency rotor in the LV maintains VF, and that spatially distributed gradients inIK1density represent a robust ionic mechanism for rotor stabilization and wavefront fragmentation.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Cardiovascular disease is the leading cause of mortality in the United States. Atherosclerosis is responsible for most of this pathology and is an inflammatory disease with multiple cytokines and adhesion molecules expressed during atherogenesis. Cytomegalovirus (CMV), monocytes, and monocyte chemoattractant protein-1 (MCP-1) have all been implicated in human atherogenesis. A transgenic mouse overexpressing MCP-1 in the myocardium and pulmonary arteries develops myocarditis and pulmonary vascular inflammation. We infected MCP-1 transgenic mice with a sublethal dose of murine cytomegalovirus (MCMV) to look for evidence of accelerated inflammation in vascular tissues overexpressing MCP-1 to determine if MCMV could interact with monocytes and MCP-1 in a manner similar to what may occur in atherogenesis. MCMV infection of MCP-1 transgenic mice caused ascites, myocarditis, and pulmonary artery inflammation, which was not present in mock-infected MCP-1 or MCMV-infected wild-type mice. Inflammatory infiltrates in these tissues consisted of macrophages and T lymphocytes similar to the infiltrates seen in atherosclerosis. Virus presence in inflamed tissues was demonstrated by infecting transgenic mice with MCMV recombinant virus containing the gene sequence for the enhanced green fluorescent protein (EGFP). Human CMV could be involved in atherogenesis in a similar manner by interacting with monocytes and MCP-1 specifically expressed in vascular walls.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

5-Hydroxytryptamine (5-HT)1Breceptors mediate contraction in human pulmonary arteries, and 5-HT1Breceptor-mediated contraction is enhanced in pulmonary arteries from hypoxic rats. Here we further examine the role of this receptor in the development of pulmonary hypertension (PHT) by examining (1) the effects of a 5-HT1B/1D-receptor antagonist (GR127935) on hypoxia-induced PHT (CHPHT) in rats and (2) CHPHT in 5-HT1B-receptor knockout mice. In rats, hypoxia increased right ventricular pressure and right ventricular hypertrophy and induced pulmonary vascular remodeling associated with an increase in pulmonary arterial wall thickness. GR127935 (3 mg · kg−1· d−1) reduced all of these indices. 5-HT1-mediated contraction was enhanced in pulmonary arteries of the CHPHT rats. The effects of GR127935 on PHT indices were associated with an attenuation of the enhanced contractile responses to 5-HT and the 5-HT1-receptor agonist, 5-carboxamidotryptamine (5-CT), in isolated pulmonary arteries. In wild-type mice, hypoxia increased right ventricular hypertrophy, which was absent in 5-HT1B-receptor knockout mice. Hypoxia increased pulmonary vascular remodeling in wild-type mice, and this was reduced in the 5-HT1B-receptor knockout mice. Hypoxia increased 5-HT1-mediated contraction in pulmonary arteries from the wild-type mice and this was attenuated in the 5-HT1B-receptor knockout mice. In conclusion, the 5-HT1Breceptor plays a role in the development of CHPHT. One possible mechanism may be via enhanced 5-HT1receptor-mediated contraction of the pulmonary arterial circulation.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Fibrinolytic activity has been reported to be decreased in atherosclerosis. Recently, annexin II was identified as a coreceptor on endothelial cells for plasminogen and tissue plasminogen activator. In this study, we examined whether recombinant annexin II (rAN II) protein can modulate fibrinolytic activity on vascular endothelium in vitro and in vivo. The effect of rAN II on human umbilical vein endothelial cells (HUVECs) was measured. Addition of a fluorescent plasmin substrate revealed that HUVECs treated with rAN II exhibited significantly more plasmin generation than those treated with BSA. Moreover, rAN II treatment of HUVECs restored plasmin generation impaired by plasminogen activator inhibitor-1 or homocysteine pretreatment. In a rat carotid artery thrombus model, the patency of thrombosed carotid arteries was significantly enhanced by rAN II injection, in contrast to BSA injection, without systemic blood coagulation dysregulation. We found that rAN II enhanced plasmin generation on vascular endothelium in vitro and reduced thrombus formation in vivo, and concluded that enhancement of endothelial fibrinolytic activity by annexin II could modulate the hypercoagulable state of atherosclerosis. Further study of rAN II in vitro and in vivo may lead to the establishment of novel therapeutic approaches to thrombogenic vascular disease.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Plasma membrane anion exchangers (AEs) regulate myocardial intracellular pH (pHi) by Na+-independent Cl−/HCO3−exchange. Angiotensin II (Ang II) activates protein kinase C (PKC) and increases anion exchange activity in the myocardium. Elevated anion exchange activity has been proposed to contribute to the development of cardiac hypertrophy. Our Northern blots showed that adult rat heart expresses AE1, AE2, AE3fl, and AE3c. Activity of each AE isoform was individually measured by following changes of pHi, associated with bicarbonate transport, in transfected HEK293 cells. Exposure to the PKC activator, PMA (150 nmol/L), increased the transport activity of only the AE3fl isoform by 50±11% (P<0.05, n=6), consistent with the increase observed in intact myocardium. Cotransfection of HEK293 cells with AE3fl and AT1a-Ang II receptors conferred sensitivity of anion transport to Ang II (500 nmol/L), increasing the transport activity by 39±3% (P<0.05, n=4). PKC inhibition by chelerythrine (10 &mgr;mol/L) blocked the PMA effect. To identify the PKC-responsive site, 7 consensus PKC phosphorylation sites of AE3fl were individually mutated to alanine. Mutation of serine 67 of AE3 prevented the PMA-induced increase of anion transport activity. Inhibition of MEK1/2 by PD98059 (50 &mgr;mol/L) did not affect the response of AE3fl to Ang II, indicating that PKC directly phosphorylates AE3fl. We conclude that following Ang II stimulation of cells, PKC&egr; phosphorylates serine 67 of the AE3 cytoplasmic domain, inducing the Ang II-induced increase in anion transport observed in the hypertrophic myocardium.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID