ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Abstract—Interleukin (IL)-18 is the interferon-&ggr;–inducing factor and has other proinflammatory properties. The precise role of IL-18 in immunoinflammatory diseases remains poorly understood. In this study, we show that in vivo electrotransfer of an expression-plasmid DNA encoding for murine IL-18 binding protein (BP) (the endogenous inhibitor of IL-18) prevents fatty streak development in the thoracic aorta of apoE knockout mice and slows progression of advanced atherosclerotic plaques in the aortic sinus. More importantly, transfection with the IL-18BP plasmid induces profound changes in plaque composition (decrease in macrophage, T cell, cell death, and lipid content and increase in smooth muscle cell and collagen content) leading to a stable plaque phenotype. These results identify for the first time a critical role for IL-18/IL-18BP regulation in atherosclerosis and suggest a potential role for IL-18 inhibitors in reduction of plaque development/progression and promotion of plaque stability. The full text of this article is available at http://www.circresaha.org.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

In recent years, there has been a sustained interest in vascularization processes. Much, if not all, of the work has included the concept of new vessel morphogenesis. Surprisingly, most of the work has not addressed developmental mechanisms directly, but rather as an offshoot of a disease process, wound healing process, or from the perspective of inducing vessels in an ischemic site. One theme has dominated the various studies on capillary or endothelial tube morphogenesis—integrin-mediated cell behavior. Integrin biology impacts virtually every known step of nascent vessel formation. In this review article, we attempted to summarize key findings from the viewpoint of developmental biologists/morphologists. We also attempted to summarize and contrast data obtained using integrin gene ablation approaches in mice with other experimental systems. It is hoped this review will provide a distinct cell biological perspective to vascular scientists from the clinical, molecular, and tissue engineering communities.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Abstract—Ahr is a ligand-activated bHLH/PAS transcription factor involved in cytochrome P450 (CYP) gene regulation and murine susceptibility to atherogenic stimuli. The present studies were conducted to examine constitutive and inducible expression ofCyp1a1andCyp1b1in vascular smooth muscle cells (VSMCs) from Ahr+/+and Ahr−/−mice.Cyp1a1mRNA was not expressed constitutively in VSMCs irrespective of Ahr phenotype. AlthoughCyp1a1was inducible in Ahr+/+by 3 &mgr;mol/L benzo(a)pyrene, a known hydrocarbon inducer, the protein was uninducible. In contrast,Cyp1b1mRNA and protein were expressed under constitutive and inducible conditions irrespective of Ahr phenotype or growth status. CYP-encoded aryl hydrocarbon hydroxylase activity was higher in Ahr−/−VSMCs under constitutive conditions and induced by benzo(a)pyrene in Ahr+/+and Ahr−/−VSMCs. CYP expression was influenced by mitogenic status, because randomly cycling cells consistently exhibited higher levels than growth-arrested counterparts. Actinomycin D (2 &mgr;g/mL) or cycloheximide (10 &mgr;mol/L) did not inhibit constitutive or hydrocarbon-inducible aryl hydrocarbon hydroxylase activity in VSMCs. These data indicate that in murine VSMCs, expression ofCyp1alandCyp1b1is differentially influenced by Ahr phenotype and mitogenic status, with patterns that may dictate inherent susceptibility to atherogenic stimuli.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Abstract—An imbalance of nitric oxide and endothelin plays an important role in cardiovascular disease. Thrombin exerts profound effects on endothelial function. The present study investigated the molecular mechanisms by which thrombin regulates endothelial nitric oxide synthase (eNOS) and endothelin-converting enzyme (ECE)-1 expression in human endothelial cells. Incubation of human umbilical vein endothelial cells with thrombin (0.01 to 4 U/mL) for 15 to 24 hours markedly downregulated eNOS and increased ECE-1 protein level in a dose-dependent manner. Thrombin also decreased eNOS mRNA and increased ECE-1 mRNA level. In mRNA stability assay, thrombin shortened the half-life of eNOS mRNA but not that of ECE-1 mRNA. Activation of protease-activated receptor 1 by the agonist (SFLLRN, 10 to 100 &mgr;mol/L) had no effect on eNOS expression but increased ECE-1 level as thrombin. Thrombin activated Rho A and extracellular signal–regulated kinase (ERK)1 and ERK2. Inhibition of Rho A by C3 exoenzyme (20 &mgr;g/mL) and ROCK by Y-27632 (10 &mgr;mol/L) prevented the downregulation of eNOS expression by thrombin. Y-27632 also prevented the reduction in NOS activity induced by prolonged incubation with thrombin. On the other hand, inhibition of ERK1 and ERK2 activation by PD98059 (50 &mgr;mol/L) prevented the upregulation of ECE-1 expression by thrombin as well as the increase in ECE activity and ET-1 accumulation in the medium. Treatment of rat aorta with thrombin overnight impaired endothelium-dependent relaxations but not endothelium-independent relaxations. Thus, thrombin suppresses eNOS and upregulates ECE-1 expression via Rho/ROCK and ERK pathway, respectively. These effects of thrombin may be important for endothelial dysfunction in cardiovascular disease, particularly during acute coronary episodes.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Abstract—Physiological and pathological cardiac hypertrophy have directionally opposite changes in transcription of thyroid hormone (TH)-responsive genes, including &agr;- and &bgr;-myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca2+-ATPase (SERCA), and TH treatment can reverse molecular and functional abnormalities in pathological hypertrophy, such as pressure overload. These findings suggest relative hypothyroidism in pathological hypertrophy, but serum levels of TH are usually normal. We studied the regulation of TH receptors (TRs) &bgr;1, &agr;1, and &agr;2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH target genes, &agr;- and &bgr;-MyHC and SERCA. All 3 TR subtypes in myocytes were downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype, phenylephrine in culture and pressure overload in vivo. Myocyte TR&bgr;1 was upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine, T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and promoters. In addition, TR cotransfection and treatment with the TR&bgr;1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TR&bgr;1 to transcription of &bgr;-MyHC, SERCA, and TR&bgr;1, and TR&agr;1 to &agr;-MyHC transcription and increased myocyte size. We conclude that TR isoforms have distinct regulation and function in rat cardiac myocytes. Changes in myocyte TR levels can explain in part the characteristic molecular phenotypes in physiological and pathological cardiac hypertrophy.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Abstract—Altered expression and functional responses to cardiac &bgr;3-adrenergic receptors (ARs) may contribute to progressive cardiac dysfunction in heart failure (CHF). We compared myocyte &bgr;3-AR mRNA and protein levels and myocyte contractile, [Ca2+]itransient, and Ca2+current (ICa,L) responses to BRL-37344 (BRL, 10−8mol/L), a selective &bgr;3-AR agonist, in 9 instrumented dogs before and after pacing-induced CHF. Myocytes were isolated from left ventricular myocardium biopsy tissues. Using reverse transcription–polymerase chain reaction, we detected &bgr;3-AR mRNA from myocyte total RNA in each animal. Using a cloned canine &bgr;3-AR cDNA probe and myocyte poly A+RNA, we detected a single band about 3.4 kb in normal and CHF myocytes. &bgr;3-AR protein was detected by Western blot. &bgr;3-AR mRNA and protein levels were significantly greater in CHF myocytes than in normal myocytes. Importantly, these changes were associated with enhanced &bgr;3-AR–mediated negative modulation on myocyte contractile response and [Ca2+]iregulation. Compared with normal myocytes, CHF myocytes had much greater decreases in the velocity of shortening and relengthening with BRL accompanied by larger reductions in the peak systolic [Ca2+]itransient andICa,L. These responses were not modified by pretreating myocytes with metoprolol (a &bgr;1-AR antagonist) or nadolol (a &bgr;1- and &bgr;2-AR antagonist), but were nearly prevented by bupranolol or L-748,337 (&bgr;3-AR antagonists). We conclude that in dogs with pacing-induced CHF, &bgr;3-AR gene expression and protein levels are upregulated, and the functional response to &bgr;3-AR stimulation is increased. This may contribute to progression of cardiac dysfunction in CHF.

ISSN:0009-7330    

出版商:OVID    

年代:2001

数据来源: OVID