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Biomedical subjects

Georg Nickenig

Publications and source records attributed to Georg Nickenig.

64 records · Page 4Linked to original sources
PubMed2002

Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production.

BACKGROUND: It has not been completely clarified whether selective estrogen receptor modulators (SERMs) such as raloxifene exert vasoprotective effects similar to those of estrogens. METHODS AND RESULTS: To investigate vascular effects of raloxifene, male spontaneously hypertensive rats were treated for 10 weeks with either raloxifene (10 mg x kg(-1) x d(-1)) or vehicle. Raloxifene improved endothelium-dependent vasodilatation but had no effect on either endothelium-independent vasorelaxation or phenylephrine-induced vasoconstriction. Raloxifene treatment increased the release of NO from the vessel wall by enhanced expression and activity of endothelial NO synthase. Blood pressure reduction after bradykinin infusion was more pronounced in animals treated with SERMs. The production of superoxide in intact aortic segments was decreased by raloxifene treatment. Administration of raloxifene had no effect on the expression of the essential NAD(P)H oxidase subunits p22phox and nox1 in the vasculature but reduced the activity and expression of vascular membrane-bound rac1, a GTPase required for the activation of the NAD(P)H oxidase. Finally, blood pressure levels were significantly decreased in spontaneously hypertensive rats treated with raloxifene. All SERM effects were also detected in healthy age-matched Wistar rats. In cultured rat aortic vascular smooth muscle cells, raloxifene inhibited angiotensin II-induced reactive oxygen species production dependent on estrogen receptor activation. CONCLUSIONS: Raloxifene treatment improves hypertension-induced endothelial dysfunction by increased bioavailability of NO. This is achieved by an increased activity of endothelial NO synthase and by an estrogen receptor-dependent reduction in release of reactive oxygen species from vascular cells. These vascular effects cause a profound blood pressure reduction and lead to decreased vascular damage in male spontaneously hypertensive rats.

Animals↗
PubMed2002

[Acute coronary syndrome--better risk stratification by determination of inflammatory parameters?].

BACKGROUND: In the past years coronary atherosclerosis and plaque rupture have been characterized not only as a problem of growth of smooth vascular cells, of activated thrombocytes and coagulation but also of inflammation. PARAMETERS OF INFLAMMATION: Several studies have demonstrated the importance of C-reactive protein as a marker for cardiovascular complications. Also interleukin-6, tumor necrosis factor-alpha and adhesion molecules are discussed as predictors of a poor prognosis in patients with acute coronary syndromes. RISK STRATIFICATION: A positive troponin T test is correlated with an increased rate of early complications; thus, these patients benefit from an aggressive therapy with GP IIb/IIIa receptor antagonists and acute coronary intervention. The C-reactive protein is predictive for late complications such as restenosis, reinfarction and death due to cardiac events; these patients benefit from close controls and from an anti-inflammatory therapy with acetylsalicyclic acid and statins.

C-Reactive Protein↗
PubMed2002

Cellular antioxidant effects of atorvastatin in vitro and in vivo.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert direct effects on vascular cells and beneficially influence endothelial dysfunction. Because reactive oxygen species (ROS) may lead to vascular damage and dysfunction, we investigated the effect of atorvastatin on ROS production and the underlying mechanisms in vitro and in vivo. Cultured rat aortic vascular smooth muscle cells were incubated with 10 micromol/L atorvastatin. Angiotensin II-induced and epidermal growth factor-induced ROS production were significantly reduced by atorvastatin (dichlorofluorescein fluorescence laser microscopy). Atorvastatin downregulated mRNA expression of the NAD(P)H oxidase subunit nox1, whereas p22phox mRNA expression was not significantly altered (reverse transcription-polymerase chain reaction, Northern analysis). Membrane translocation of rac1 GTPase, which is required for the activation of NAD(P)H oxidase, was inhibited by atorvastatin (Western blot). mRNA expression of superoxide dismutase isoforms and glutathione peroxidase was not modified by atorvastatin, whereas catalase expression was upregulated at mRNA and protein levels, resulting in an increased enzymatic activity. Effects of atorvastatin on ROS production and nox1, rac1, and catalase expression were inhibited by L-mevalonate but not by 25-hydroxycholesterol. In addition, spontaneously hypertensive rats were treated with atorvastatin for 30 days. ROS production in aortic segments was significantly reduced in statin-treated rats (lucigenin chemiluminescence). Treatment with atorvastatin reduced vascular mRNA expression of p22phox and nox1 and increased aortic catalase expression. mRNA expression of superoxide dismutases, glutathione peroxidase, and NAD(P)H oxidase subunits gp91phox, p40phox, p47phox, and p67phox remained unchanged. Translocation of rac1 from the cytosol to the cell membrane was also reduced in vivo. Thus, atorvastatin exerts cellular antioxidant effects in cultured rat vascular smooth muscle cells and in the vasculature of spontaneously hypertensive rats mediated by decreased expression of essential NAD(P)H oxidase subunits and by upregulation of catalase expression. These effects of atorvastatin may contribute to the vasoprotective effects of statins.

Animals↗
PubMed2002

Destabilization of AT(1) receptor mRNA by calreticulin.

AT(1) receptor activation leads to vasoconstriction, blood pressure increase, free radical release, and cell growth. AT(1) receptor regulation contributes to the adaptation of the renin-angiotensin system to long-term stimulation and serves as explanation for the involvement of the AT(1) receptor in the pathogenesis of cardiovascular disease. The molecular mechanisms involved in AT(1) receptor regulation are poorly understood. Here, we report that angiotensin II accelerates AT(1) receptor mRNA decay in vascular smooth muscle cells. A cognate mRNA region within the 3' untranslated region at bases 2175 to 2195 governs the inducible decay of the AT(1) receptor mRNA. Sequential protein purifications led to the discovery of a novel mRNA binding protein, calreticulin, which mediates destabilization of the AT(1) receptor mRNA. Angiotensin II-caused phosphorylation of calreticulin enables binding of calreticulin to the AT(1) receptor mRNA at bases 2175 to 2195 and propagates calreticulin-induced acceleration of AT(1) receptor mRNA decay. Thus, a novel mRNA binding protein, calreticulin, is discovered, which causes AT(1) receptor mRNA degradation via binding to a distinct mRNA region in the 3' untranslated region. These findings display a novel mechanism of posttranscriptional mRNA processing.

Angiotensin II↗
PubMed2002

Pleiotropic effects of HMG-CoA reductase inhibitors.

HMG CoA reductase inhibitiors (statins) have been shown to be effective lipid lowering agents and are able to significantly reduce cardiovascular mortality and morbidity in patients at risk for cardiovascular disease. Recent clinical and experimental data suggest that the benefit of statins may extend beyond their hepatic effects on serum cholesterol levels. This review summarizes the current evidence and the molecular mechanisms of the direct effects of statins on plaque stability, inflammation, endothelial function, oxidative stress, thrombosis and stroke. Furthermore, recent data on the effects of statins on bone marrow, bone density and dementia are described. In summary, statins have emerged as a novel and powerful tool to study cardiovascular biology, including protein isoprenylation, small G protein function, leukocyte activity and endothelial progenitor cells. These pleiotropic properties of statins may have important clinical implications in addition to lowering serum cholesterol.

Coronary Disease↗
PubMed2002

Impact of HMG CoA reductase inhibition on small GTPases in the heart.

OBJECTIVE: Members of the Rho GTPase family, Rac1 and RhoA have been suggested to be mediators of cardiac hypertrophy in mice. Rho proteins are posttranslationally isoprenylated. In addition to cholesterol-lowering, statins inhibit the isoprenylation of small G proteins. Therefore, it was tested if these drugs inhibit Rac1 and RhoA activity in cardiomyocytes and, thereby, prevent angiotensin II-mediated expression of atrial natriuretic factor (ANF) and myosin light chain (MLC)-2 in the heart. METHODS AND RESULTS: Western and Northern analysis of rat neonatal cardiomyocytes and H9C2 cells showed inhibition of basal and angiotensin-stimulated Rac1 expression, membrane-translocation and activity after statin treatment. Similarly, basal and stimulated RhoA membrane expression was inhibited. Statins concentration- and time-dependently downregulated basal as well as angiotensin-induced expression of ANF by 86+/-2.3% and 89+/-1.7%, as well as MLC-2 by 75+/-4.1% and 84+/-6%, respectively. Direct inhibition of Rac GTPase by overexpression of the dominant negative mutant RacN17 or by Clostridium sordellii lethal toxin in rat H9C2 cells inhibited ANF expression by 70+/-4.9% and 78+/-10%, respectively. Inhibition of RhoA by Clostridium botulinum C3 transferase or the dominant negative mutant RhoN19 reduced ANF mRNA by 19+/-11% and 23+/-8%, respectively. To test these findings in vivo, spontaneously hypertensive rats were treated with atorvastatin, leading to a decrease in cardiac Rac1 and RhoA activity as determined by [35S]-GTP gamma S-binding assays by 61+/-16% and 72+/-24%, and downregulation of MLC-2 as well as ANF mRNA expression by 31+/-16% and 80+/-24%, respectively. CONCLUSIONS: (1) Statins downregulate the activity of small G proteins in cardiomyocytes in culture as well as in vivo. (2) Inhibition of Rac1 and RhoA by statins reduces myocardial expression of ANF and MLC-2. (3) Targeting myocardial Rho GTPases by statins may be a novel treatment strategy to prevent cardiac hypertrophy.

Angiotensin II↗
PubMed2002

Redox-sensitive vascular smooth muscle cell proliferation is mediated by GKLF and Id3 in vitro and in vivo.

Reactive oxygen species such as superoxide and hydroxyl radicals have been implicated in the pathogenic growth of various cell types. The molecular mechanisms involved in redox-sensitive cell growth control are poorly understood. Stimulation of cultured vascular smooth muscle cells (VSMC) with xanthin/xanthin oxidase (X/XO) increases proliferation, whereas stimulation with hydrogen peroxide and Fe3+NTA (H-Fe) causes growth arrest of VSMC. Differential Display led to the identification of two novel, differentially regulated redox-sensitive genes. The dominant negative helix-loop-helix protein Id3 is induced by X/XO and down-regulated by H-Fe. The transcription factor gut-enriched Kruppel-like factor (GKLF) is induced by H-Fe but not by X/XO. Induction of GKLF and inhibition of Id3 via transfection experiments leads to growth arrest, whereas overexpression of Id3 and inhibition of GKLF cause cell growth. Id3 down-regulation is induced via binding of GKLF to the Id3 promotor and concomitantly reduced Id3 gene transcription rate. GKLF induction by H-Fe is mediated through hydroxyl radicals, p38MAP kinase-, calcium-, and protein synthesis-dependent pathways. Id3 is induced by X/XO via superoxide, calcium, p38, and p42/44 MAP kinase. GKLF induces and Id3 depresses expression of p21WAF1/Cip1, p27KIP1, p53. Induction of Id3 is accomplished by angiotensin II via superoxide release. A vascular injury mouse model revealed that Id3 is overexpressed in proliferating vascular tissue in vivo. These findings reveal novel mechanisms of redox-controlled cellular proliferation involving GKLF and Id3 that may have general implications for our understanding of vascular and nonvascular growth control.

Angiotensin II↗
PubMed2002

Improvement of Endothelial Function by HMG-CoA Reductase Inhibitors.

Endothelial dysfunction is the early and crucial state of atherosclerosis that is associated with a poor prognosis. Mechanistically, endothelial dysfunction is caused by reduced nitric oxide bioactivity. HMG-CoA reductase inhibitors (statins) effectively lower cholesterol plasma levels and profoundly decrease the cardiovascular risk of hypercholesterolemic patients. It is well established that statins improve endothelial dysfunction in those patients. The underlying mechanisms are less clear. It is thought that pleiotrophic, cholesterol-independent effects of statins such as increase of nitric oxide bioactivity and reduction of oxidative stress may contribute to the vasoprotective effects of statins. Therefore, it is speculated that statins, at least in part, improve endothelial function independent of plasma cholesterol concentrations and may thereby exert beneficial clinical effects. This notion of statins as general atheroprotective drugs has been underlined by in vitro experiments, animal studies and small clinical trials. However, large-scale clinical intervention studies are needed to confirm a positive influence of statins on endothelial dysfunction and cardiac event rates in normochlesterolemic patients. (c) 2002 Prous Science. All rights reserved.

Journal Article↗