ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundHypoxia and indirect angiogenic factors may stimulate angiogenesis via induction of endothelial cell mitogen(s). To evaluate this hypothesis, we investigated whether low oxygen tension or cytokines known to promote neovascularization in vivo could modulate the expression of either vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) in human vascular smooth muscle cells (SMCs).Methods and ResultsSMCs were treated with platelet-derived growth factor BB (PDGF-BB) or transforming growth factor-β1(TGF-β1) or exposed to low oxygen tension in serum-free medium. Northern analysis detected low basal levels of VEGF and bFGF mRNA in extracts of unstimulated SMCs. However, both VEGF and bFGF transcripts increased after administration of PDGF-BB (10 or 20 ng/mL) or TGF-β1(0.1 to 10 ng/mL). Hypoxia was a potent stimulus for VEGF gene expression but had no apparent effect on bFGF steady-state mRNA levels.ConclsionsThese results indicate that certain indirect angiogenic cytokines, such as PDGF-BB or TGF-β1, may act via induction of bFGF and VEGF gene expression in cells resident near endothelial cells in vivo. Hypoxia constitutes a potent stimulus for VEGF gene expression but does not regulate bFGF under the same experimental conditions.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundObservations of abnormalities in the diastolic components of intracellular Ca2+transiPnts in failing human left ventricular myocardium have raised the possibility that reductions in the level or function of sarcoplasmic reticulum proteins involved in Ca2+transport contribute to the patho-physiology of dilated cardiomyopathy in humans. Functional assays, however, have revealed no differences in ATP-depen-dent Ca2+transport or its modulation by phospholamban in sarcoplasmic reticulum-enriched microsomes prepared from nonfailing and failing human left ventricular myocardium. The purpose of the present study was to quantify protein levels of Ca2+−transporting ATPase, phospholamban, and calsequestrin directly in nonfailing and failing human left ventricular myocardium.Methods and ResultsTotal protein extracts were prepared from nonfailing left ventricular myocardium from the hearts of unmatched organ donors with normal left ventricular contractility (n=6) and from failing left ventricular myocardium from the excised hearts of transplant recipients with class IV heart failure resulting from idiopathic dilated cardiomyopathy (n=6). Ca2+−transporting ATPase, phospholamban, and calse-questrin contents were determined by quantitative immunoblotting with monoclonal and affinity-purified polyclonal antibodies. The levels of the three proteins were identical in nonfailing and failing human left ventricular myocardium.ConclusionsThese results indicate that protein levels of Ca2+−transporting ATPase, phospholamban, and calsequestrin are not diminished in failing human left ventricular myocardium and that downregulation of the Ca2+−transporting ATPase and phospholamban is not part of the molecular pathophysiology of dilated cardiomyopathy in humans.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundEndothelium-dependent vasodilation in response to acetylcholine (ACh) and ischemic vasodilation during reactive hyperemia are attenuated in the forearm of patients with heart failure (HF). It has been shown that L-arginine augments endothelium-dependent vasodilation in healthy subjects. Thus, the aim of the present study was to determine if L-arginine improves endothelium-dependent and ischemic vasodilation in the forearm in HF.Methods and ResultsForearm blood flow was measured by a strain-gauge plethysmograph in 20 patients with HF and in 24 age-matched control subjects (C). Resting forearm vascular resistance (FVR) was significantly higher in HF than in C (37±4 versus 22±2 U,P<.01). Intra-arterial infusions of ACh or sodium nitroprusside (SNP) at graded doses progressively decreased FVR in HF as well as in C. The magnitude of ACh-induced vasodilation was attenuated in HF (P<.01), whereas SNP-induced vasodilation was similar between the two groups. The minimal FVR during reactive hyperemia after 10 minutes of arterial occlusion was significantly higher in HF (n= 12) than in C (n= 12) (3.2±0.4 versus 2.1±0.1 U,P<.05). L-Arginine significantly augmented maximal vasodilation evoked with ACh and decreased minimal FVR during reactive hyperemia in HF (P<.01) but not in C. L-Arginine did not affect SNP-induced vasodilation in HF or C.ConclusionsOur results suggest that defective endothelial function may contribute to impaired ischemic vasodilator capacity in HF.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundThe angiotensin-converting enzyme (ACE) plays an important role in the production of angiotensin II and the degradation of bradykinin, two peptides involved in cardiovascular homeostasy. Presence of a polymorphism in the ACE gene (ACESs) has been postulated from segregation analysis of plasma ACE in families. This putative polymorphism, which strongly affects the plasma and cellular levels of ACE, probably by modulating ACE gene transcription, has not yet been identified at the molecular level; however, an insertion/ deletion polymorphism is present in the 16th intron of the ACE gene (ACE I/D) and appears to be a very good marker for ACE Ss. The biological role of ACE suggests that the ACE gene polymorphism could affect the predisposition to myocardial infarction (MI).Methods and ResultsWe have recently shown, in a large case-control study (ECTIM), that the marker allele D of the ACE gene, which is associated with higher levels of ACE in plasma and cells, was more frequent in male patients with MI than in control subjects, especially in patients considered at low risk. ACE activity has now been measured from frozen aliquots of plasma in a large subsample of the ECTIM study (n=1086). Plasma ACE level did not differ between patients and control subjects in the older age group (≥55 years) but was higher in patients than in control subjects in the younger age group (<55 years);P<.005 after adjustment on ACE I/D and other risk factors. In patients, plasma ACE levels decreased with age (R= −.225,P< 10−4), but in control subjects no such trend was observed. In the low-risk group (ApoB <1.25 mg/dL, body mass index <26 kg/m2, and not treated with hypolipidemic drugs), plasma ACE level was increased in patients when compared with control subjects among homozygotes and heterozygotes for the ACE I allele (P<.015). Analysis of the distribution of plasma ACE by using commingling analysis conditional on the marker genotype ACE I/D enabled us to infer the frequencies and effects of the postulated ACESsgenotypes. The results suggest that the higher plasma ACE levels in patients than in control subjects in the younger age group were due to a difference in frequency of the postulated S allele (.47 versus.36).ConclusionsThese results extend our previous findings and indicate that plasma ACE level may be a risk factor for MI, independent of the ACE I/D polymorphism.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundFurther understanding of cardiac allograft vasculopathy (CAV) is needed to improve long-term survival after cardiac transplantation. The diffuse hyperplasia of coronary intima characteristic of CAV suggests that growth factors may play a role in the development of CAV. Fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) are potent mitogens for smooth muscle cells (SMCs), and PDGF is an important cofactor in the pathogenesis of native coronary atherosclerosis.Methods and ResultsReverse transcriptase/polymerase chain reaction (RT/PCR), in situ hybridization, and immuno-histochemistry were used to determine whether transplantation results in increased cardiac expression of acidic (a)FGF, basic (b)FGF, and PDGF-A and -B chains. Sixty-eight myo-cardial biopsies from 36 heart transplant recipients and 7 normal hearts were analyzed by PCR. aFGF mRNA was present in 54 of 61 allograft biopsies and was not found in any normal heart. In situ hybridization and immunohistochemistry demonstrated diffuse, intense expression of aFGF mRNA and protein in allograft biopsies, predominantly in myocytes and vascular walls. Only scattered aFGF expression was observed in normal hearts. mRNA for the full-length isoform of PDGF-A chain was found in 43 of 61 allograft biopsies and was not detected in any normal heart. In situ hybridization and immunohistochemistry confirmed that full-length PDGF-A chain mRNA and PDGF protein were present in myocytes and vascular walls.ConclusionsExpression of aFGF and PDGF-A chain is significantly increased in cardiac allografts. Cardiac myocytes and vascular walls are the predominant sources of aFGF and PDGF. Diffuse expression of these growth factors in cardiac allografts may be important in the pathogenesis of CAV.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundCellular rejection of an allograft is mediated in part by peripheral blood T cells. We tested the hypothesis that quantitative changes in T-cell subsets can be detected in the peripheral blood and that these changes correlate with rejection.Methods and ResultsT-cell subset analysis was performed by flow cytometry using monoclonal antibodies recognizing six isotypic epitopes of the T-cell receptor β-chain variable (V) region. These analyses were done at 7-day (mean) time intervals. Fluctuations within a given subset were determined by dividing the number of positive cells observed by the number of positive cells found on the previous analysis. For healthy volunteers observed over a period of 30 days, 119 of 120 subset ratios (99.2%) fell between 0.5 and 2.0. For patients, 57 of 240 subset ratios (23.8%) fell outside of this range (P<.004,X2). The occurrence of the abnormal ratios coincided more closely with cellular rejection (mean±SD, 7.7±6.2 days from a positive biopsy; median, 5 days; range, 0 to 28 days) than did the occurrence of normal subset ratios (mean±SD, 14.4±10.9 days from a positive biopsy; median, 11 days; range, 0 to 44 days;P<.005 by Mann-WhitneyUtest). Regression analysis confirmed a significant (P<.001,R=.91) temporal association between cellular rejection and abnormal subset fluctuations. No correlation was found between abnormal subset ratios and either vascular rejection or use of high-dose prednisone.ConclusionsT-cell subset measurement may be a method of noninvasive monitoring of cellular rejection after transplantation and may provide insights into the physiology of graft rejection with the potential for the development of more specific immunosuppressive therapy.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundThere is growing evidence for a pathogenic role for cytokines in atherogenesis. The presence of certain cytokines has been documented in human atherosclerotic vessels. This study was designed to investigate cytokine production by mononuclear leukocytes from patients with ischemic heart disease.Methods and ResultsWe measured kinetics of secretion of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) by mononuclear leukocytes from 8 control subjects, 10 patients with stable angina pectoris, and 10 patients with unstable angina pectoris. Mononuclear leukocytes were isolated and incubated with or without the plant lectin mitogen concanava-lin A for 48 hours. TNF-α and IFN-γ secretion were measured by ELISA. The effect of TNF-α and IFN-γ on superoxide radical generation by neutrophils was also examined. Secretion of both TNF-α and IFN-γ by mononuclear leukocytes increased progressively over 48 hours, and it was consistently higher (P<.02) in patients compared with control subjects. A similar increase in cytokine secretion was observed in patients with stable or unstable angina pectoris. In addition, there was no relation between the severity of coronary artery disease by angiography and cytokine secretion. Basal neutrophil superoxide radical generation was increased in patients with ischemic heart disease, and incubation with cytokines failed to further stimulate superoxide generation in these patients.ConclusionsSimilar increases in cytokine secretion by mononuclear leukocytes in stable or unstable angina pectoris indicate that the increased cytokine release is not a nonspecific inflammatory response in acute myocardial ischemia. Increased cytokine secretion in ischemic heart disease may play a role in superoxide radical generation, endothelial injury, deposition and activation of cellular elements on the vessel wall, and possibly in the progression of atherosclerosis.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

BackgroundBrief episodes of ischemia render the heart more resistant to subsequent ischemia; this phenomenon has been called ischemic preconditioning. In some animal species, myocardial preconditioning appears to be due to activation of ATP-sensitive K+(KATP) channels. The role played by KATPchannels in preconditioning in humans remains unknown. The aim of this study was to establish whether glibenclamide, a selective KATPchannel blocker, abolishes the ischemic preconditioning observed in humans during coronary angioplasty following repeated balloon inflations.Methods and ResultsTwenty consecutive patients undergoing one-vessel coronary angioplasty were randomized to receive 10 mg oral glibenclamide or placebo. Sixty minutes after glibenclamide or placebo administration, patients were given an infusion of 10% dextrose (8 mL/min) to correct glucose plasma levels or, respectively, an infusion of saline at the same infusion rate. Thirty minutes after the beginning of the infusion, both patient groups underwent coronary angioplasty. The mean values (± 1 SD) of ST-segment shifts on the surface 12-lead ECG and the intracoronary ECG were measured at the end of the first and second balloon inflations, both 2 minutes long. In glibenclamide-treated patients, the mean ST-segment shift during the second balloon inflation was similar to that observed during the first inflation (23± 13 versus 20±8 mm,P=NS), and the severity of cardiac pain was greater (55±21 versus 43±23 mm on a scale of 0 to 100,P<.05). Conversely, in placebo-treated patients the mean ST-segment shift during the second inflation was less than that during the first inflation (9±5 versus 23±13 mm,P<.001), as was the severity of cardiac pain (15±15 versus 42±19 mm,P<.01). Blood glucose levels were significantly reduced 60 minutes after glibenclamide compared with those at baseline (53±9 versus 102±10 mg/100 mL,P<.001) in the glibenclamide group; however, before coronary angioplasty, blood glucose levels increased to 95±19 mg/100 mL, a value similar to that found in placebo group (96±11 mg/100 mL,P=NS).ConclusionsIn humans, ischemic preconditioning during brief repeated coronary occlusions is completely abolished by pretreatment with glibenclamide, thus suggesting that it is mainly mediated by KATPchannels.

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID