摘要:

Carbon monoxide (CO) is generated in living organisms during the degradation of heme by the enzyme heme oxygenase, which exists in constitutive (HO-2 and HO-3) and inducible (HO-1) isoforms. Carbon monoxide gas is known to dilate blood vessels in a manner similar to nitric oxide and has been recently shown to possess antiinflammatory and antiapoptotic properties. We report that a series of transition metal carbonyls, termed here carbon monoxide-releasing molecules (CO-RMs), liberate CO to elicit direct biological activities. Specifically, spectrophotometric and NMR analysis revealed that dimanganese decacarbonyl and tricarbonyldichlororuthenium (II) dimer release CO in a concentration-dependent manner. Moreover, CO-RMs caused sustained vasodilation in precontracted rat aortic rings, attenuated coronary vasoconstriction in hearts ex vivo, and significantly reduced acute hypertension in vivo. These vascular effects were mimicked by induction of HO-1 after treatment of animals with hemin, which increases endogenously generated CO. Thus, we have identified a novel class of compounds that are useful as prototypes for studying the bioactivity of CO. In the long term, transition metal carbonyls could be utilized for the therapeutic delivery of CO to alleviate vascular- and immuno-related dysfunctions. The full text of this article is available at http://www.circresaha.org.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Vascular endothelial growth factor (VEGF) expression is upregulated by hypoxia-inducible factor-1 (HIF-1) in ischemic tissues and growing tumors. Normally, HIF-1 activity depends on the amount of HIF-1&agr; subunit, which is tightly regulated by the oxygen tension. In the myocardium, VEGF expression has been shown to be induced under nonhypoxic conditions by mechanical stresses. However, the cellular mechanism of stress-mediated VEGF induction remains unclear. Therefore, we examined the possible involvement of HIF-1 in stress-mediated VEGF induction in rat hearts. In this study, we increased the left ventricular wall tension using 3 different methods, namely by inducing regional ischemia, by expanding an intraventricular balloon, and by producing hemodynamic overload using an aortocaval shunt. In all cases, HIF-1&agr; accumulated in the nuclei of cardiac myocytes in the early phase, and this was followed by VEGF induction. Phosphatidylinositol 3-kinase (PI3K)–dependent Akt phosphorylation was found to be activated by mechanical stress and completely blocked by wortmannin (a PI3K inhibitor). Moreover, the stress-mediated induction of HIF-1&agr; and VEGF was suppressed by gadolinium (a stretch-activated channel inhibitor), wortmannin, and rapamycin (a FRAP inhibitor). Our results suggest that HIF-1&agr; plays an important role in the induction of VEGF in nonischemic and mechanically stressed myocardium, and that this is regulated by stretch-activated channels and the PI3K/Akt/FRAP pathway. Moreover, this signaling pathway, which induces HIF-1&agr;, seems to play an important role in the adaptation of the myocardium to stresses. The full text of this article is available at http://www.circresaha.org.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We have previously shown that interferon-&ggr; (IFN-&ggr;) is a potent enhancer of atherogenesis. Interleukin-18 (IL-18) promotes inflammatory responses through release of IFN-&ggr;, although it can also exert direct actions on other inflammatory mediators. In this present study, we determined the effects of IL-18 on atherogenesis and the role of IFN-&ggr; in this response. Male apolipoprotein E−/−mice (apoe−/−; aged 16 weeks, n=10/group) were fed a normal diet and injected intraperitoneally for 30 days with either recombinant IL-18 (30 ng/g/day) or saline. Atherosclerotic lesion size was quantified in 2 vascular beds: the ascending aorta and the aortic arch. IL-18 administration did not affect serum cholesterol concentrations or lipoprotein-cholesterol distribution; however, exogenous IL-18 administration increased lesion size 2-fold in both the ascending aorta (50 642±12 515 versus 112 399±13 227 &mgr;m2,P=0.004; saline versus IL-18 groups, respectively) and the aortic arch (3.1±0.3% versus 6.2±0.9% area,P=0.006). Exogenous IL-18 promoted a 4-fold increase in the number of lesion-associated T lymphocytes (11±3 versus 50±5 cells;P<0.0001) and cells expressing major histocompatability complex class II (9±3 versus 40±6 cells;P=0.0002). To determine the role of IFN-&ggr; production in this response, exogenous IL-18 was administered toapoe−/−mice that were IFN-&ggr; deficient. These studies demonstrated that lack of endogenous IFN-&ggr; ablated the effects of IL-18 on atherosclerosis. Therefore, these data strongly implicates IL-18 in the atherogenic process and suggests that IL-18 increases lesion development through enhancement of an inflammatory response involving an IFN-&ggr;–dependent mechanism. The full text of this article is available at http://www.circresaha.org.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Exposure of rats to 10% O2for 4 days caused pulmonary hypertension and induced expression of both inducible nitric oxide synthase (iNOS) and CCAAT box enhancer binding protein-&bgr; (C/EBP-&bgr;) in rat lung. Electrophoretic mobility shift assays (EMSAs) showed that exposure to 1% O2increased the C/EBP-&bgr; binding in rat pulmonary microvascular smooth muscle cells (rPSMs). To test the hypothesis that C/EBP-&bgr; participates in hypoxia-induced iNOS expression in rPSMs, a C/EBP motif at −910 bp of rat iNOS promoter was mutated. rPSMs transfected with the rat iNOS promoter and exposed to 1% O2for 24 hours had significantly increased wild-type iNOS promoter activity. The hypoxia-induced promoter activity was abolished by the C/EBP motif mutation. Thus, C/EBP-&bgr; mediates, at least in part, hypoxia-induced iNOS expression in rPSMs.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Cardiotrophin-1 (CT-1), a member of the interleukin-6 superfamily, and endothelin-1 (ET-1) are potent hypertrophic factors in cardiomyocytes. Although CT-1 and ET-1 gene expression in the heart is upregulated in experimental heart failure, their role in the activation of the cardiac fibroblast is unknown. This study was designed to identify the presence and action of CT-1 and its receptor complex, glycoprotein130 (gp130) and leukemia inhibitory factor (LIF) receptor, on cardiac fibroblast growth in cultured adult canine cardiac fibroblasts. In addition, we investigated the interaction between CT-1/gp130/LIF receptor and ET-1/endothelin type A (ETA) receptor axis. Immunohistochemistry was performed using the indirect immunoperoxidase method, while we assessed the cell cycle of cardiac fibroblasts by flow cytometry, DNA synthesis by [3H]thymidine incorporation, and collagen synthesis by [3H]proline incorporation, respectively. CT-1 and gp130/LIF receptor were widely present in the cytoplasm of the cardiac fibroblasts. Exogenous CT-1 markedly stimulated [3H]thymidine and [3H]proline incorporations (P<0.01), with accumulation of cells in the S phase. Blockade of gp130 or LIF receptor inhibited basal growth as well as CT-1– or ET-1–stimulated cardiac fibroblast growth. The specific ETAreceptor antagonist, BQ123, significantly inhibited CT-1–stimulated DNA synthesis. This study demonstrates that CT-1 and its receptors are present in cardiac fibroblasts. In addition, growth of these cells stimulated by endogenous and exogenous CT-1 requires gp130/LIF receptor as well as ETAreceptor activation. We conclude that gp130/LIF receptor and ETAreceptor activation are essential for cardiac fibroblast growth by CT-1 and that there is synergism with ET-1/ETAreceptor axis.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Angiotensin II (Ang II) may cause cardiac hypertrophy via type 1 Ang II receptors (AT1) on cardiomyocytes and through growth factors released from cardiac fibroblasts. Whereas cardiomyocyte-specific AT1receptor expression produces cardiac hypertrophy and remodeling in vivo, delineation of the signals that mediate growth to Ang II is challenging because the prevailing in vitro model (cultured neonatal cardiomyocytes) expresses low levels of AT1receptor and responds inconsistently to Ang II. In this study, when AT1Areceptors were expressed using adenovirus in cultured neonatal cardiomyocytes, Ang II stimulated a robust hypertrophy that was not secondary to the release of cardiac fibroblast-derived factors, specifically endothelin-1. Hypertrophy was accompanied by the induction of the immediate-early response genes,c-fosandc-jun, and reexpression of atrial natriuretic peptide (ANP). Ang II–induced activation of an ANP promoter-reporter was inhibited by the dominant/negative mutants, G&agr;qI and N17Ras, indicating that hypertrophic signaling by the AT1Areceptor is via heterotrimeric G protein coupling and downstream Ras pathways. AT1A-mediated cardiomyocyte hypertrophy and mitogen-activated protein kinase (MAPK) activation were inhibited by the MAPK kinase inhibitor, PD98059, and the epidermal growth factor (EGF) receptor kinase antagonist, AG1478, but not by PKC inhibitor, bisindolylmaleimide-1. Moreover, Ang II–induced MAPK activation was prevented by treatment with a matrix metalloproteinase inhibitor, consistent with the tyrosine phosphorylation of the EGF receptor in response to AT1Areceptor activation. These data unequivocally demonstrate that Ang II can directly promote cardiac myocyte growth via AT1Areceptors expressed on these cells and reveal for the first time the important contribution of EGF receptor–transactivated MAPK signaling to this process.

ISSN:0009-7330    

出版商:OVID    

年代:2002

数据来源: OVID