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Biomedical subjects

G W De Keulenaer

Publications and source records attributed to G W De Keulenaer.

13 recordsLinked to original sources
PubMed2001

Activation of cardiac endothelium as a compensatory component in endotoxin-induced cardiomyopathy: role of endothelin, prostaglandins, and nitric oxide.

BACKGROUND: In view of growing evidence of an important endothelial paracrine regulation of cardiac function, the present study investigated the role of cardiac endothelium-derived endothelin-1 (ET-1), prostaglandins, and nitric oxide (NO) during endotoxin-induced cardiomyopathy in rabbits. METHODS AND RESULTS: Immunohistochemical studies showed a marked transient coinduction of the inducible isoforms of NO synthase (NOS-2) and cyclooxygenase (COX-2) in endocardial endothelium and coronary arteriolar endothelium of hearts 12 hours after intravenous administration of lipopolysaccharide (LPS+12h); staining for both isoforms was much weaker 24 hours later (LPS+36h). Nitrotyrosine localization was similar to that of NOS-2, suggesting a NOS-2-related endothelial formation of peroxynitrite in septic hearts. Contractile performance of papillary muscles was depressed in both LPS-treated groups. In the LPS+12h group, however, isometric twitches were significantly prolonged (482+/-14 versus 420+/-14 ms in the saline-treated group, P<0.005). This twitch prolongation was completely reversed by simultaneous administration of BQ-123 and indomethacin to block endogenous ET-1 and prostaglandins, respectively. In addition, in the LPS+12h group, myocardial inotropic responsiveness to exogenous ET-1 was enhanced (P<0.01). CONCLUSIONS: Cardiac endothelial activation and myocardial sensitization to endothelium-derived mediators may be part of an adaptive response in the early (12 hours) stages of septic cardiomyopathy.

Animals↗
PubMed2000

Convergence of redox-sensitive and mitogen-activated protein kinase signaling pathways in tumor necrosis factor-alpha-mediated monocyte chemoattractant protein-1 induction in vascular smooth muscle cells.

Monocyte chemoattractant protein-1 (MCP-1) is an important component of the inflammatory response of the vessel wall and has been shown to be regulated by cytokines, such as tumor necrosis factor-alpha (TNF-alpha). However, the precise signaling pathways leading to MCP-1 induction have not been fully elucidated in vascular smooth muscle cells (VSMCs). Cytokine signal transduction involves protein kinases as well as reactive oxygen species (ROS). The relation between these 2 factors is not clear. In this study, we show that TNF-alpha induces a parallel phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) and increases MCP-1 mRNA expression in cultured VSMCs. Inhibition of ERK1/2 but not p38MAPK caused a partial attenuation of MCP-1 induction (43+/-10% inhibition). Incubation of VSMCs with multiple antioxidants (diphenylene iodonium, liposomal superoxide dismutase, catalase, N-acetylcysteine, dimethylthiourea, and pyrrolidine dithiocarbamate) had no effect on TNF-alpha-mediated MCP-1 upregulation. However, simultaneous blockade of the ERK1/2 and ROS pathways by using PD098059 combined with diphenylene iodonium or N-acetylcysteine potently enhanced the ability of MAPK kinase inhibitors to abrogate MCP-1 mRNA expression (100+/-2% inhibition). Thus, parallel ROS-dependent and ERK1/2-dependent pathways converge to regulate TNF-alpha-induced MCP-1 gene expression in VSMCs. These data unmask a complex but organized integration of ROS and protein kinases that mediates cytokine-induced vascular inflammatory gene expression.

Animals↗
PubMed1998

Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide-producing NADH oxidase.

Atherosclerotic lesions are found opposite vascular flow dividers at sites of low shear stress and oscillatory flow. Since endothelial proinflammatory genes prominent in lesions are regulated by oxidation-sensitive transcriptional control mechanisms, we examined the redox state of cultured human umbilical vein endothelial cells after either oscillatory or steady laminar fluid shear stress. Endothelial oxidative stress was assessed by measuring activity of the superoxide (O2.- )-producing NADH oxidase (a major source of reactive oxygen species in vascular cells), intracellular O2.- levels, induction of the redox-sensitive gene heme oxygenase-1 (HO-1), and abundance of Cu/Zn superoxide dismutase (Cu/Zn SOD), an antioxidant defense enzyme whose level of expression adapts to changes in oxidative stress. When cells were exposed to oscillatory shear (+/-5 dyne/cm2, 1 Hz) for 1, 5, and 24 hours, NADH oxidase activity and the amount of HO-1 progressively increased up to 174+/-16% (P<0.05) and 505+/-111% (P<0.05) versus static conditions, respectively, whereas levels of Cu/Zn SOD remained unchanged. This upregulation of HO-1 was completely blocked by the antioxidant N-acetylcysteine (NAC, 20 mmol/L). In contrast, steady laminar shear (5 dyne/cm2) induced NADH oxidase activity and NAC-sensitive HO-1 mRNA expression only at 1 and 5 hours, a transient response that returned toward baseline at 24 hours. Levels of Cu/Zn SOD mRNA and protein were increased after 24 hours of steady laminar shear. Furthermore, intracellular O2.-, as measured by dihydroethidium fluorescence, was higher in cells exposed to oscillatory than to laminar shear. These data are consistent with the hypothesis that continuous oscillatory shear causes a sustained activation of pro-oxidant processes resulting in redox-sensitive gene expression in human endothelial cells. Steady laminar shear stress initially activates these processes but appears to induce compensatory antioxidant defenses. We speculate that differences in endothelial redox state, orchestrated by different regimens of shear stress, may contribute to the focal nature of atherosclerosis.

Arteriosclerosis↗
PubMed1998

Tumour necrosis factor alpha activates a p22phox-based NADH oxidase in vascular smooth muscle.

Increasing experimental evidence suggests that non-phagocytic cells express a potent superoxide (O2-.)-producing NADH oxidase that might be related to the phagocytic NADPH oxidase. Here we show that the cytokine tumour necrosis factor alpha (TNF-alpha) activates, in a time- and dose-dependent manner, a O2-.-producing NADH oxidase in cultured rat aortic smooth-muscle cells. Dose-response experiments for NADH showed an upward shift of the curve for TNF-alpha-treated cells, suggesting that TNF-alpha increased the amount of available enzyme. Using the anti-sense transfection technique, we further demonstrate that the molecular identity of this oxidase includes p22(phox) (the alpha subunit of cytochrome b558 and part of the electron transfer component of the phagocytic NADPH oxidase), which we recently cloned from a rat vascular smooth-muscle cell cDNA library. In addition, prolonged treatment with TNF-alpha increased p22phox mRNA expression without affecting p22phox mRNA stability, and only when transcriptional activity was intact. These findings identify a p22phox-containing NADH oxidase as a source for cytokine-induced free radical production in vascular smooth-muscle cells and clarify some of the mechanisms involved in the regulation of vascular oxidase activity.

Animals↗
PubMed1998

Reappraisal of the multicellular preparation for the in vitro physiopharmacological evaluation of myocardial performance.

In order to evaluate myocardial performance, single cardiomyocytes suffer from technical problems and from the fact that some basic functional properties vanish when one moves down the hierarchic scale from multicellularity to single cells. The isolated papillary muscle has at present proven to be superior to the isolated intact cardiomyocyte. A large number of major intra- and extracellular features required to describe myocardial performance can be derived from analyzing twitch contraction and relaxation in the multicellular isolated papillary muscle. In addition, the present paper illustrates the possibility to differentiate between effects of inotropic interventions on activating Ca2+ and Ca2+ sensitivity in multicellular preparations, from a grid analysis of isometric twitches in a coordinate system of peak rate of force development (+dF/dt; reflecting the time pattern of twitch contraction) versus time to half relaxation (tHR; reflecting the time pattern of twitch relaxation). The abundance of information about myocardial performance that can be derived from the easily accessible multicellular preparation reflects its physiological kinship with the intact ventricle.

Animals↗
PubMed1998

Cardiac endothelium and myocardial function.

Endocardial endothelium and vascular endothelium of myocardial capillaries share common features as modulators of cardiac performance, rhythmicity and growth. Growing evidence suggests differences between these two cardiac endothelial cell types with regard to developmental, morphological and functional properties. A major difference probably resides in the way and extent by which these endothelial cells perceive and transmit signals.

Animals↗
PubMed1998

Pathogenesis of heart failure. Changing conceptual paradigms.

Experimental observations, made over the past two decades, have led to a profound shift in the conceptual paradigms about the syndrome of heart failure. As a consequence, heart failure is nowadays considered as a complex disease, not merely characterized by haemodynamic disturbances. Instead, it is now believed that the syndrome is governed and impelled by neurohumoral imbalances and by intracardiac paracrine processes. The latter processes are mediated by activated cardiac endothelial cells and by cytokines, creating a state of cardiac maladaption and leading to disease progression. The clinical benefit of several therapeutic interventions that could not be satisfactorily clarified by improvements in the haemodynamic status, may, therefore, be explained by an unexpected impact on cytokines and endothelial dysfunction. Further extension of these insights will form the basis for the future treatment of heart failure.

Animals↗
PubMed1996

Endocardial endothelial dysfunction and heart failure.

Like vascular endothelium, the EE plays a role in transendothelial transport, in coagulant and thrombotic processes, and in interactions with inflammatory cells. In addition, EE is involved in the modulation of cardiac performance of subjacent myocardium. EE dysfunction includes insufficient as well as excessive performance of any of its multiple functions. Dysfunction can progress from a disturbed modulation of myocardial performance and an imbalance in the release of growth factors to changes in EE cytoskeletal organization, with concomitant changes in transendothelial permeability, and in extreme cases, to loss of endothelial integrity and frank denudation. Structural and functional impairment of EE and of endocardial interstitial cells may be primary or secondary to the disease. Mechanical stress, various hormones and cytokines can initiate EE dysfunction. EE dysfunction may influence the development of cardiac failure in endo(myo)cardial fibrosis (Loeffler's endocarditis and carcinoid syndrome) and in dilated cardiomyopathy. Although Bouillaud, in 1836, was referring to endocarditis when stating: (quote: see text) his statement may presently find a much broader field of applicability in cardiology.

Animals↗
PubMed1995

Endothelin-mediated positive inotropic effect induced by reactive oxygen species in isolated cardiac muscle.

Cardiac endothelium, both coronary and endocardial, produces a number of inotropic molecules. Changes in cardiac endothelial function by substances in the superfusing blood may thus participate in the control of muscle-pump performance of the heart. Reactive oxygen species (ROS) have been implicated in normal and pathological vascular physiology by influencing vascular endothelial function. Therefore, we examined the influence of ROS on endocardial endothelial modulation of myocardial performance. Right ventricular cat papillary muscles were briefly (15 s) exposed to electrolysis-generated ROS. Peak total isometric twitch tension and peak rate of tension development increased by 7.8 +/- 0.7% (P < .05) and 9.7 +/- 1.5% (P < .05), respectively (n = 12). Isometric twitch duration was slightly increased (time from stimulus to half isometric relaxation, +2.7 +/- 0.6%; P < .05). ROS scavengers such as ascorbic acid (n = 6), superoxide dismutase and catalase (n = 8), or catalase alone (n = 6), but not superoxide dismutase alone (n = 6), blocked the inotropic effect. Interestingly, the positive inotropic effect was completely blocked by selectively damaging endocardial endothelium (Triton X-100, 0.5%, 1-s immersion, n = 7) before ROS generation and by preincubating the muscles with the endothelin-A receptor antagonist BQ 123 (n = 11). Preincubation with NG-nitro-L-arginine methyl ester and indomethacin (n = 5) or with atenolol (n = 6) did not influence the inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

The cardiac endothelium: functional morphology, development, and physiology.

Cardiac endothelial cells, regardless of whether they are from endocardial or from coronary (micro)vascular origin, directly modulate performance of the subjacent cardiomyocytes, resulting in control of the onset of ventricular relaxation and rapid filling of the heart. This review summarizes major features of the morphology, embryology, and comparative physiology of cardiac endothelial cells as well as the experimental observations on how cardiac endothelial cells affect the mechanical performance of the heart. As for the underlying mechanisms of the interaction between cardiac endothelial cells and cardiomyocytes, two working hypotheses have been postulated over the past years; (1) interaction mediated through a trans-endothelial physicochemical gradient for various ions (active blood-heart barrier), and (2) interaction mediated through the release by the cardiac endothelial cells of various cardioactive substances, eg, nitric oxide, endothelin, and prostacyclin. These two mechanisms may act in concert or in parallel.

Animals↗
PubMedDate not supplied

Dilated cardiomyopathy: changing pathophysiological concepts and mechanisms of dysfunction.

Experimental observations made over the past two decades have led to a profound shift in the conceptual paradigms about the syndrome of heart failure and dilated cardiomyopathy. As a consequence, heart failure is currently considered a complex disease and is not merely characterized by hemodynamic disturbances. It is now believed that the syndrome is governed and impelled by neurohormonal imbalances and intracardiac paracrine processes. The latter processes are mediated by activated cardiac endothelial cells and cytokines, creating a state of cardiac maladaption and leading to disease progression. Therapeutic interventions such as operative left ventricular volume reduction or mitral valve reconstruction should therefore no longer be solely interpreted in terms of hemodynamics (i.e., symptomatic improvements). Effects on neurohormonal, endothelial, and cytokine activities should be taken equally into account.

Cardiomyopathy, Dilated↗