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Biomedical subjects

G Nickenig

Publications and source records attributed to G Nickenig.

65 records · Page 4Linked to original sources
PubMed1997

Alpha-adrenergic signal transduction in renin transgenic rats.

The alpha1-adrenoceptor-G protein-phosphoinositide-specific phospholipase C (PLC) signal transduction pathway is assumed to play an important role in the regulation of contractile force and in the pathophysiology of myocardial hypertrophy. In the present study, the components of this pathway were investigated in left ventricles of hearts from hypertensive transgenic rats overexpressing the mouse renin gene [TG(mREN2)27] in comparison to age- and weight-matched Sprague-Dawley control rats. Contractile force was assessed in isolated electrically driven left ventricular papillary muscle strips. Alpha1-adrenoceptor density was measured by radioligand binding using [3H]prazosin, steady state levels of alpha q/11, and G protein beta-subunits by Western blotting. PLC activity was determined by a cell-free assay using exogenous phospholipid vesicles containing [3H]phosphatidylinositol (4,5)-bisphosphate as a substrate. Alpha1-adrenoceptor density was significantly increased (by 80%) in transgenic rats compared with control rats, while the positive inotropic response to the alpha1-adrenoceptor agonist phenylephrine was significantly reduced, suggesting a postreceptor defect in TG(mREN2)27. The expression of alpha q and alpha11 was verified by reverse transcription-polymerase chain reaction, and alpha q/11 steady state protein levels were shown to be similar in transgenic and control rats. Western blotting using a beta-common antibody revealed two bands at approximately 35 and 36 kD. The quantities of both were similar in TG(mREN2)27 compared with those in control rats. In contrast, PLC activity was significantly reduced (by 32%) in transgenic rats. In conclusion, our findings are consistent with a desensitization of the alpha1-adrenergic signal transduction pathway at the level of the effector.

Animals↗
PubMed1996

[Swelling of the ears, chest pain, cough].

A 62-year-old male had tender swelling of both ears with loss of hearing due to edematous swelling of the external auditory canal. The patient complained further about dry cough, pain at the costo-sternal junctions, adynamia and weight loss. Inflammatory parameters were markedly elevated, and histologic work-up of an auricular biopsy revealed lymphocytic infiltration. These findings led to the diagnosis of chronic recurrent polychondritis actually under control after a pulse of glucocorticoids followed by maintenance therapy with 5 mg prednisone.

Chest Pain↗
PubMed1996

Regulation of angiotensin AT1 receptor gene expression during cell growth of vascular smooth muscle cells.

Cell proliferation influences the expression of numerous tissue-specific genes. The angiotensin AT1 receptor is highly expressed on vascular smooth muscle cells where it mediates cell contraction upon activation with angiotensin II. Since vascular smooth muscle cell de-differentiation leads to differential expression of several genes, we investigated the effects of cell growth on angiotensin AT1 receptor gene expression in vascular smooth muscle cells in culture. Northern hybridization analysis revealed a decrease of angiotensin AT1 receptor mRNA levels to approximately 20% in proliferating cells in comparison to growth-arrested cells. There is a correlative loss of membrane-associated angiotensin AT1 receptor protein in growing cells versus non-growing cells, as assessed by saturation radioligand binding assays. In addition, the BB-isoform of platelet-derived growth factor (PDGF-BB), which induces proliferation of quiescent vascular smooth muscle cells, causes a marked down-regulation of angiotensin AT1 receptor mRNA. These data suggest that proliferation of vascular smooth muscle cells leads to reduced angiotensin AT1 receptor gene expression. The mechanisms underlying this process and its physiological implications remain to be defined.

Animals↗
PubMed1996

Enhanced angiotensin receptor type 1 mRNA degradation and induction of polyribosomal mRNA binding proteins by angiotensin II in vascular smooth muscle cells.

Stimulation of cultured rat thoracic aorta vascular smooth muscle cells (VSMCs) with 100 nM angiotensin II (Ang II) reduces angiotensin receptor type 1 (AT1-R) gene expression. mRNA levels are reduced to approximately 30% of control levels 4 hr after the addition of Ang II to the culture medium. The loss of mRNA remains sustained for up to 24 hr after the addition of Ang II. The half-life of the AT1-R mRNA is approximately 2 hr in cells treated with a single dose of 100 nM Ang II. This represents a 3-fold reduction from its half-life of 6 hr in nonstimulated cells, as assessed by treatment with 5,6-dichlorobenzimidazole or actinomycin D to block transcription. Thus, the AT1-R mRNA is moderately unstable in VSMC and destabilized further by treatment with Ang II. Ang II-induced AT1-R mRNA destabilization is prevented by pretreatment with transcriptional inhibitors or the protein synthesis inhibitor cycloheximide, suggesting that Ang II-induced AT1-R mRNA destabilization requires the induction of an unknown factor or factors that are postulated to mediate this effect. AT1-R mRNA levels decrease more rapidly in vitro from a polyribosomal fraction isolated from VSMC exposed for 2 hr to 100 nM Ang II compared with that from vehicle-treated cells, suggesting that polyribosomal-associated AT1-R mRNA is at least one site of action for the mRNA destabilization effect of Ang II. Ang II stimulation induces a complex of polyribosomal proteins that bind specifically in the distal 350 bases of the AT1-R mRNA. Regulation of mRNA stability accounts in part for modulation of AT1-R gene expression by Ang II in VSMCs, and Ang II-induced AT1-R mRNA polyribosomal binding proteins are associated with this phenomenon.

Angiotensin I↗
PubMed1995

Angiotensin II down-regulates the vascular smooth muscle AT1 receptor by transcriptional and post-transcriptional mechanisms: evidence for homologous and heterologous regulation.

The vascular angiotensin II (ANG II) receptor (AT1) is a central component of the renin-angiotensin system; thus, regulation of its expression is likely to be important in cardiovascular responsiveness. We demonstrate that ANG II down-regulates its receptor in rat aortic vascular smooth muscle cells. Incubation for 4 hr with 100 nM ANG II decreased AT1 mRNA and protein by 70% and 35%, respectively. This homologous down-regulation was concentration and time dependent and was blocked by the AT1 antagonist losartan. It did not appear to be mediated by protein kinase C or other protein kinases but was dependent on the sustained signaling pathway sensitive to phenylarsine oxide. Heterologous down-regulation was observed with the agonists alpha-thrombin and ATP and the cAMP-increasing agent forskolin. ANG II inhibited transcription by 50% and destabilized the AT1 mRNA. Down-regulation of AT1 mRNA was blocked by transcription and translation inhibitors, suggesting that it required expression of a protein factor or factors. These results indicate that ANG II down-regulates its vascular receptor by both transcriptional and post-transcriptional mechanisms. Homologous and heterologous down-regulation of the AT1 receptor may participate in the coordinated physiological adaptation of vascular tone to vasoactive hormones.

Adenosine Triphosphate↗
PubMed1994

Oxymetazoline enhances epidermal- and platelet-derived growth factor-induced DNA synthesis.

In the present study, the effect of 10(-9) to 10(-6) M epinephrine (alpha- and beta-agonist), norepinephrine (alpha- and beta 1-antagonist) isoproterenol (beta-agonist) salbutamol (beta 2-agonist), phenylephrine (alpha 1-agonist) and oxymetazoline (mainly alpha 2-agonist) on DNA synthesis in vascular smooth muscle cells (VSMCs) from rat aorta has been investigated. Our results show that only oxymetazoline induced a moderate dose-dependent elevation of [3H]thymidine incorporation into cell DNA (10(-6) M, 100-300%). Epidermal growth factor (EGF) (50 ng/ml) and platelet-derived growth factor (PDGF)-BB induced an elevation of the [3H]thymidine incorporation into cell DNA from 154 +/- 7 (basal value) to 1270 +/- 95 and 1552 +/- 178 cpm/microgram protein (mean +/- S.D., n = 3). Oxymetazoline (10(-6) M) and phenylephrine induced an increase of [3H]thymidine incorporation to 368 +/- 53 and 205 +/- 27 cpm/microgram protein, respectively. In contrast to phenylephrine, oxymetazoline caused an elevation of the PDGF-BB- and EGF-induced [3H]thymidine incorporation to 1561 +/- 143 and 2086 +/- 235 (means S.D., n = 3), respectively. In addition, EGF (1 to 50 ng/ml) induced a dose-dependent increase of [3H]thymidine incorporation from 154 +/- 7 (basal value) to 486 +/- 35 (1 ng/ml), 912 +/- 74 (5 ng/ml), 1019 +/- 40 (25 ng/ml) and 1270 +/- 95 (50 ng/ml) cpm/microgram protein (mean +/- S.D.). In the presence of 10(-6) M oxymetazoline, 1, 5, 25 and 50 ng/ml EGF caused an increase of [3H]thymidine incorporation to 633 +/- 101, 1124 +/- 87, 1231 +/- 101, and 1561 +/- 89 cpm/microgram protein (mean +/- S.D.).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Agonists↗
PubMed1994

Down-regulation by growth factors of vascular smooth muscle angiotensin receptor gene expression.

The effects of epidermal growth factor, basic fibroblast growth factor, and platelet-derived growth factor-BB on angiotensin type 1 (AT1) receptor gene expression were examined in rat thoracic aorta vascular smooth muscle cells (VSMC) in culture. Incubation of serum-deprived VSMC with 20 ng/ml epidermal growth factor, 20 ng/ml basic fibroblast growth factor, or 50 ng/ml platelet-derived growth factor-BB reduces AT1 receptor mRNA levels, as assessed by Northern hybridization analysis, to approximately 30% of control levels. This effect is maximal 4 hr after addition of each growth factor to the culture medium and is sustained for up to 24 hr of incubation after a single dose. There is a correlative loss of membrane-associated AT1 receptors and angiotensin II-stimulated inositol phosphate production after 24 hr of growth factor treatment. The half-life of AT1 receptor mRNA is reduced significantly by growth factors, compared with that for cells treated with actinomycin D alone to block transcription. This suggests that growth factors activate a mechanism that involves post-transcriptional destabilization of AT1 receptor mRNA. This effect can be blocked by prior treatment of VSMC with actinomycin D or cycloheximide, suggesting that the effect of the growth factors on AT1 receptor gene expression is mediated through induction of an unknown gene or genes that function to destabilize AT1 receptor mRNA and that mRNA translation is essential for the destabilizing effect. Nuclear run-on assays reveal that the growth factors also significantly reduce the rate of de novo AT1 receptor gene transcription. Thus, down-regulation of AT1 receptor gene expression by growth factors also appears to involve mechanisms that decrease the rate of AT1 receptor gene transcription. These data reveal marked down-regulation of AT1 receptor gene expression in VSMC by growth factor receptor activation, through mechanisms that involve both attenuation of transcription and post-transcriptional mRNA destabilization.

Animals↗
PubMed1993

Synergistic action of angiotensin II, insulin-like growth factor-I, and transforming growth factor-beta on platelet-derived growth factor-BB, basic fibroblastic growth factor, and epidermal growth factor-induced DNA synthesis in vascular smooth muscle cells.

The effect of angiotensin II (AII), transforming growth factor-beta (TGF-beta), and insulin-like growth factor-I (IGF-I) on platelet-derived growth factor (PDGF)-BB-, basic fibroblastic growth factor (bFGF)-, and epidermal growth factor (EGF)-induced DNA synthesis in vascular smooth muscle cells (VSMCs) was investigated. TGF-beta, AII, IGF-I increased concentration-dependent cell protein. No increase in [3H]thymidine incorporation could be detected. TGF-beta, AII, and IGF-I enhanced PDGF-BB-, bFGF-, and EGF-induced DNA synthesis. Our results suggest that growth factors that possess a weak mitogenic effect on vascular smooth muscle cells such as TGF-beta, AII, and IGF-I may enhance the mitogenicity of PDGF-BB, bFGF, and EGF.

Angiotensin II↗
PubMedDate not supplied

Clinical and therapeutical implications of EPC biology in atherosclerosis.

Bone marrow-derived circulating endothelial progenitor cells have been successfully used to enhance angiogenesis after tissue ischemia. The role of endothelial progenitor cells in endothelial cell homeostasis and their putative role in atherogenesis have been recently investigated. Cardiovascular risk factors negatively influence endothelial progenitor cell number and function while vasculoprotection e.g. by statins, estrogens and physical activity may be partly mediated by progenitor cells. Endogenous mobilization or injection of ex-vivo generated endothelial progenitor cells is associated with an enhanced reendothelialization, an improvement of endothelial function and reduced atherosclerotic burden. In contrast, endothelial progenitor cells may promote plaque angiogenesis in animal models and may negatively influence plaque development and stability. However, in humans with coronary atherosclerotic disease, endothelial progenitor cells are a novel risk predictor for cardiovascular mortality and morbidity. In this review we focus on the role of circulating endothelial progenitor cells in endothelial cell repair mechanisms at the vascular wall and their potentially protective and therapeutic role in atherosclerotic disease.

Atherosclerosis↗