Huige Li - Academia.edu (original) (raw)

Papers by Huige Li

Research paper thumbnail of Effects of nitroglycerin treatment on NOSIII gene expression and superoxide production

Free Radical Biology and Medicine

Research paper thumbnail of Red Wine Increases the Expression of Human Endothelial Nitric Oxide Synthase

Journal of the American College of Cardiology

The study tested the effect of red wine on endothelial-type nitric oxide synthase (eNOS) expressi... more The study tested the effect of red wine on endothelial-type nitric oxide synthase (eNOS) expression and eNOS activity in human endothelial cells. BACKGROUND Endothelial-type nitric oxide (NO) synthase exerts vasoprotective effects. Moderate alcohol consumption has been associated with a reduction of cardiovascular disease, and red wine seems to offer more benefits than any other type of drink. However, the molecular basis of this protective effect is unclear.

Research paper thumbnail of Dual Effect of Ceramide on Human Endothelial Cells

Circulation

Background-Generation of the second-messenger molecule ceramide by stimulated sphingomyelinase ac... more Background-Generation of the second-messenger molecule ceramide by stimulated sphingomyelinase activity has been implicated in the inflammatory processes contributing to the pathogenesis of atherosclerosis. However, reports of stimulatory effects of ceramide on endothelial NO production in animal models suggest antiatherosclerotic effects of the molecule. Therefore, we investigated long-term effects of ceramide on NO generation in human endothelial cells. Methods and Results-In human umbilical vein endothelial cells (HUVECs) and in HUVEC-derived EA.hy 926 endothelial cells, C6-ceramide (N-hexanoyl-D-erythro-sphingosine) reduced the generation of bioactive NO (RFL-6 reporter-cell assay). At the same time, the signaling molecule increased endothelial NO synthase (eNOS) mRNA (RNase protection assay) and protein expression (Western blot). C6-ceramide stimulated eNOS transcription by a signaling mechanism involving protein phosphatase PP2A but did not modify the stability of the eNOS mRNA. Endothelial generation of reactive oxygen species (ROS) was increased by C6-ceramide [5-(and-6)-chloromethyl-2Ј,7Ј-dichlorodihydrofluorescein diacetate (CM-H 2 DCFDA) oxidation-based fluorescence assay], and this effect was partially reversed by the NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME). On the other hand, (6R)-5,6,7,8-tetrahydro-Lbiopterin (BH 4 ) normalized in part the ceramide-induced reduction in bioactive NO. Conclusions-Ceramide produces oxidative stress in human endothelial cells, thereby reducing bioactive NO. The partial reversal of this reduction by BH 4 and the diminution of ROS generation by L-NAME suggest that ceramide promotes NADPH oxidase activity of eNOS, leading to ROS formation at the expense of NO synthesis. The ceramide-induced upregulation of eNOS gene transcription can be considered an ineffective compensatory mechanism. The decreased bioavailability of NO is likely to favor a proatherogenic role of ceramide. (Circulation. 2002;106:2250-2256.)

Research paper thumbnail of The role of nitric oxide synthase in diabetes mellitus

Free Radical Biology and Medicine

Research paper thumbnail of Molecular Mechanisms on How Resveratrol Enhances Endothelial NO Production

https://www.novapublishers.com/catalog/product\_info.php?products\_id=34278

Research paper thumbnail of P378 RESVERATROL REVERSES eNOS UNCOUPLING: IMPLICATION OF SIRT1

Atherosclerosis Supplements, 2010

Research paper thumbnail of Anti-Inflammatory and Anti-Thrombotic Effects of the Fungal Metabolite Galiellalactone in Apolipoprotein E-Deficient Mice

PLOS ONE, 2015

Patients suffering from chronic inflammatory diseases have an increased mortality risk resulting ... more Patients suffering from chronic inflammatory diseases have an increased mortality risk resulting from cardiovascular disorders due to enhanced atherosclerotic and thrombotic events. Until now, it is not completely understood in which way an abnormal expression of pro-inflammatory mediators contributes to this elevated cardiovascular risk, but there is a need for new drugs that on the one hand suppress the expression of pro-inflammatory mediators and on the other hand inhibit arterial platelet adhesion. Thus, we analyzed the anti-inflammatory and anti-thrombotic capacity of the fungal metabolite Galiellalactone in atherosclerosis-prone apolipoprotein E-deficient mice. Treatment of the mice with Galiellalactone lowered the inflammatory expression profile and improved blood clotting times, as well as platelet adhesion to the injured common carotid artery. The results indicate that administration of Galiellalactone is able to reduce the extent of inflammation and arterial platelet adhesion in this mouse model.

Research paper thumbnail of Nebivolol Inhibits Superoxide Formation by NADPH Oxidase and Endothelial Dysfunction in Angiotensin II-Treated Rats

Nebivolol is a 1-receptor antagonist with vasodilator and antioxidant properties. Because the vas... more Nebivolol is a 1-receptor antagonist with vasodilator and antioxidant properties. Because the vascular NADPH oxidase is an important superoxide source, we studied the effect of nebivolol on endothelial function and NADPH oxidase activity and expression in the well-characterized model of angiotensin II-induced hypertension. Angiotensin II infusion (1 mg/kg per day for 7 days) caused endothelial dysfunction in male Wistar rats

Research paper thumbnail of Inhibitors of Histone Deacetylation Downregulate the Expression of Endothelial Nitric Oxide Synthase and Compromise Endothelial Cell Function in Vasorelaxation and Angiogenesis

Research paper thumbnail of Downregulation of BDNF Expression by PKC and by TNF-α in Human Endothelial Cells

Pharmacology, Jan 28, 2015

Brain-derived neurotrophic factor (BDNF) is a neurotrophin best characterized for its survival an... more Brain-derived neurotrophic factor (BDNF) is a neurotrophin best characterized for its survival and differentiative effects on neurons. Recent studies demonstrated that BDNF and its receptors are also expressed in the peripheral vasculature, where it stimulates angiogenesis and promotes the survival of endothelial cells. This study was designed to investigate the angiogenic effects of BDNF and its expressional regulation by tumor necrosis factor (TNF-α) and protein kinase C (PKC) in endothelial cells. In the Matrigel angiogenesis assay, BDNF-stimulated vascular tube formation of human umbilical vein endothelial cells (HUVEC) was completely blocked by an inhibition of the TrkB receptor, but only partially inhibited by the inhibition of the p75(NTR) signaling. Treatment of HUVEC and HUVEC-derived EA.hy 926 cells with TNF-α resulted in a downregulation of BDNF expression, which could be prevented by the TNFR1 antagonist WP9QY. BDNF downregulation by TNF-α was associated with decreased a...

Research paper thumbnail of NO Synthesis and NOS Regulation

Signal Transduction by Reactive Oxygen and Nitrogen Species: Pathways and Chemical Principles, 2004

Page 1. Chapter 7 NO SYNTHESIS AND NOS REGULATION Ulrich Forstermann, Huige Li, Petra M. Schwarz ... more Page 1. Chapter 7 NO SYNTHESIS AND NOS REGULATION Ulrich Forstermann, Huige Li, Petra M. Schwarz and Hartmut Kleinert 7.1 Introduction Nature has turned to nitric oxide (NO), a small bioactive gas, to mediate vital servoregulatory as well as cytotoxic functions. ...

Research paper thumbnail of Nitric Oxide: Biological Synthesis and Functions

Gasotransmitters: Physiology and Pathophysiology, 2012

ABSTRACT The pluripotent gaseous messenger molecule nitric oxide (NO) controls vital functions su... more ABSTRACT The pluripotent gaseous messenger molecule nitric oxide (NO) controls vital functions such as neurotransmission or vascular tone (via activation of soluble guanylyl cyclase), gene transcription, mRNA translation (via iron-responsive elements), and post-translational modifications of proteins (via ADP-ribosylation). In higher concentrations, NO is capable of destroying parasites and tumor cells by inhibiting iron-containing enzymes or directly interacting with the DNA of these cells. In view of this multitude of functions of NO, it is important to understand the mechanisms by which cells accomplish and regulate the production of this molecule. In mammals, three isozymes of NO synthase (NOS; L-arginine, NADPH:oxygen oxidoreductases, nitric oxide forming; EC 1.14.13.39) have been identified. These isoforms are referred to as neuronal “n”NOS (or NOS I), inducible “i”NOS (or NOS II), and endothelial “e”NOS (or NOS III). In pathophysiology, massive amounts of NO produced by hyperactive nNOS or highly expressed iNOS can contribute to processes such as neurodegeneration, inflammation, and tissue damage. This chapter will describe principles of NO biosynthesis, regulatory mechanisms controlling the production of this molecule, and the large array of (physiologic and pathophysiologic) functions that Mother Nature has assigned to this small messenger molecule.

Research paper thumbnail of Resveratrol as a gene regulator in the vasculature

Current pharmaceutical biotechnology, 2014

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) possesses multiple protective properties in th... more Resveratrol (3,5,4'-trihydroxy-trans-stilbene) possesses multiple protective properties in the vasculature, including anti-oxidative and anti-inflammatory effects and improvement of endothelial function. A substantial part of these effects is attributable to gene expression changes induced by the compound. Resveratrol can activate the NAD-dependent deacetylase sirtuin 1 (SIRT1), leading to deacetylation of SIRT1 target molecules such as NF-kB and forkhead box O (FOXO) transcription factors. The inhibition of NF-kB by resveratrol reduces the expression of inflammation mediators. FOXO factors are implicated in the upregulation of antioxidant enzymes and the endothelial-type nitric oxide synthase. In addition, resveratrol upregulates a number of antioxidant enzymes by activating nuclear factor-E2-related factor-2 (Nrf2) and downregulates NADPH oxidases through yet known mechanisms.

Research paper thumbnail of Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease

Arteriosclerosis, thrombosis, and vascular biology, 2014

Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory ski... more Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease. Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17A(ind/+) mice), associated with increased reactive oxygen species formation and circulating CD11b(+) inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls. In K14-IL-17A(ind/+) mice, immunohistochemistry and flow cytometry revealed increased vascular production of the nitric oxide/superoxide reaction product peroxynitrite and infiltration of the vasculature with myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) cells accompanied b...

Research paper thumbnail of Resveratrol and endothelial nitric oxide

Molecules (Basel, Switzerland), 2014

Nitric oxide (NO) derived from the endothelial NO synthase (eNOS) has antihypertensive, antithrom... more Nitric oxide (NO) derived from the endothelial NO synthase (eNOS) has antihypertensive, antithrombotic, anti-atherosclerotic and antiobesogenic properties. Resveratrol is a polyphenol phytoalexin with multiple cardiovascular and metabolic effects. Part of the beneficial effects of resveratrol are mediated by eNOS. Resveratrol stimulates NO production from eNOS by a number of mechanisms, including upregulation of eNOS expression, stimulation of eNOS enzymatic activity and reversal of eNOS uncoupling. In addition, by reducing oxidative stress, resveratrol prevents oxidative NO inactivation by superoxide thereby enhancing NO bioavailability. Molecular pathways underlying these effects of resveratrol involve SIRT1, AMPK, Nrf2 and estrogen receptors.

Research paper thumbnail of Dexamethasone upregulates Nox1 expression in vascular smooth muscle cells

Pharmacology, 2014

It has been demonstrated that dexamethasone-induced hypertension can be prevented by the NADPH ox... more It has been demonstrated that dexamethasone-induced hypertension can be prevented by the NADPH oxidase inhibitor apocynin. The effect of dexamethasone on NADPH oxidase, however, is unknown. The present study was conducted to investigate the effect of dexamethasone on the gene expression of Nox1, the major NADPH oxidase isoform in vascular smooth muscle cells. Oral treatment of Wistar-Kyoto rats with dexamethasone (0.03 mg/kg/day) for 12 days led to an upregulation of Nox1 mRNA expression in the aorta. In cultured A7r5 rat aortic smooth muscle cells, dexamethasone increased Nox1 mRNA expression in a concentration- and time-dependent manner. The upregulation of Nox1 mRNA expression was completely prevented by the glucocorticoid receptor antagonist mifepristone. The effect of dexamethasone on Nox1 expression was likely to be indirect as it could be largely blocked by cycloheximide, an inhibitor of protein biosynthesis. Dexamethasone increased Nox1 mRNA stability as well as Nox1 transcr...

Research paper thumbnail of Pharmacological prevention of eNOS uncoupling

Current pharmaceutical design, 2014

Under physiological conditions, nitric oxide (NO) is produced in the vasculature mainly by the en... more Under physiological conditions, nitric oxide (NO) is produced in the vasculature mainly by the endothelial NO synthase (eNOS). This endothelium-derived NO is a protective molecule with antihypertensive, antithrombotic and anti-atherosclerotic properties. Cardiovascular risk factors such as hypertension, hypercholesterolemia, cigarette smoking and diabetes mellitus induce oxidative stress mostly by stimulation of the NADPH oxidase. Overproduction of reactive oxygen species leads to oxidation of tetrahydrobiopterin (BH4), the essential cofactor of eNOS. In BH4 deficiency, oxygen reduction uncouples from NO synthesis, thereby converting eNOS to a superoxide- producing enzyme. Consequently, NO production is reduced and the pre-existing oxidative stress is enhanced, which contribute significantly to cardiovascular pathology. Therefore, pharmacological approaches that prevent eNOS uncoupling are of therapeutic interest. Among the drugs currently in clinical use, the renin inhibitor aliski...

Research paper thumbnail of Biphasic regulation of NADPH oxidase expression by protein kinase C in human endothelial cells

GBM Annual Spring meeting Mosbach 2006, 2006

Research paper thumbnail of Vascular oxidative stress, nitric oxide and atherosclerosis

Atherosclerosis, 2014

In the vascular wall, reactive oxygen species (ROS) are produced by several enzyme systems includ... more In the vascular wall, reactive oxygen species (ROS) are produced by several enzyme systems including NADPH oxidase, xanthine oxidase, uncoupled endothelial nitric oxide synthase (eNOS) and the mitochondrial electron transport chain. On the other hand, the vasculature is protected by antioxidant enzyme systems, including superoxide dismutases, catalase, glutathione peroxidases and paraoxonases, which detoxify ROS. Cardiovascular risk factors such as hypercholesterolemia, hypertension, and diabetes mellitus enhance ROS generation, resulting in oxidative stress. This leads to oxidative modification of lipoproteins and phospholipids, mechanisms that contribute to atherogenesis. In addition, oxidation of tetrahydrobiopterin may cause eNOS uncoupling and thus potentiation of oxidative stress and reduction of eNOS-derived NO, which is a protective principle in the vasculature. This review summarizes the latest advances in the role of ROS-producing enzymes, antioxidative enzymes as well as NO synthases in the initiation and development of atherosclerosis.

Research paper thumbnail of Role of nitric oxide synthase isoforms for ophthalmic artery reactivity in mice

Experimental Eye Research, 2014

Nitric oxide synthases (NOS) are involved in regulation of ocular vascular tone and blood flow. W... more Nitric oxide synthases (NOS) are involved in regulation of ocular vascular tone and blood flow. While endothelial NOS (eNOS) has recently been shown to mediate endothelium-dependent vasodilation in mouse retinal arterioles, the contribution of individual NOS isoforms to vascular responses is unknown in the retrobulbar vasculature. Moreover, it is unknown whether the lack of a single NOS isoform affects neuron survival in the retina. Thus, the goal of the present study was to examine the hypothesis that the lack of individual nitric oxide synthase (NOS) isoforms affects the reactivity of mouse ophthalmic arteries and neuron density in the retinal ganglion cell (RGC) layer. Mice deficient in one of the three NOS isoforms (nNOS-/-, iNOS-/- and eNOS-/-) were compared to respective wild type controls. Intraocular pressure (IOP) was measured in conscious mice using rebound tonometry. To examine the role of each NOS isoform for mediating vascular responses, ophthalmic arteries were studied in vitro using video microscopy. Neuron density in the RGC layer was calculated from retinal wholemounts stained with cresyl blue. IOP was similar in all NOS-deficient genotypes and respective wild type controls. In ophthalmic arteries, phenylephrine, nitroprusside and acetylcholine evoked concentration-dependent responses that did not differ between individual NOS-deficient genotypes and their respective controls. In all genotypes except eNOS-/- mice, vasodilation to acetylcholine was markedly reduced after incubation with L-NAME, a non-isoform-selective inhibitor of NOS. In contrast, pharmacological inhibition of nNOS and iNOS had no effect on acetylcholine-induced vasodilation in any of the mouse genotypes. Neuron density in the RGC layer was similar in all NOS-deficient genotypes and respective controls. Our findings suggest that eNOS contributes to endothelium-dependent dilation of murine ophthalmic arteries. However, the chronic lack of eNOS is functionally compensated by NOS-independent vasodilator mechanisms. The lack of a single NOS isoform does not appear to affect IOP or neuron density in the RGC layer.

Research paper thumbnail of Effects of nitroglycerin treatment on NOSIII gene expression and superoxide production

Free Radical Biology and Medicine

Research paper thumbnail of Red Wine Increases the Expression of Human Endothelial Nitric Oxide Synthase

Journal of the American College of Cardiology

The study tested the effect of red wine on endothelial-type nitric oxide synthase (eNOS) expressi... more The study tested the effect of red wine on endothelial-type nitric oxide synthase (eNOS) expression and eNOS activity in human endothelial cells. BACKGROUND Endothelial-type nitric oxide (NO) synthase exerts vasoprotective effects. Moderate alcohol consumption has been associated with a reduction of cardiovascular disease, and red wine seems to offer more benefits than any other type of drink. However, the molecular basis of this protective effect is unclear.

Research paper thumbnail of Dual Effect of Ceramide on Human Endothelial Cells

Circulation

Background-Generation of the second-messenger molecule ceramide by stimulated sphingomyelinase ac... more Background-Generation of the second-messenger molecule ceramide by stimulated sphingomyelinase activity has been implicated in the inflammatory processes contributing to the pathogenesis of atherosclerosis. However, reports of stimulatory effects of ceramide on endothelial NO production in animal models suggest antiatherosclerotic effects of the molecule. Therefore, we investigated long-term effects of ceramide on NO generation in human endothelial cells. Methods and Results-In human umbilical vein endothelial cells (HUVECs) and in HUVEC-derived EA.hy 926 endothelial cells, C6-ceramide (N-hexanoyl-D-erythro-sphingosine) reduced the generation of bioactive NO (RFL-6 reporter-cell assay). At the same time, the signaling molecule increased endothelial NO synthase (eNOS) mRNA (RNase protection assay) and protein expression (Western blot). C6-ceramide stimulated eNOS transcription by a signaling mechanism involving protein phosphatase PP2A but did not modify the stability of the eNOS mRNA. Endothelial generation of reactive oxygen species (ROS) was increased by C6-ceramide [5-(and-6)-chloromethyl-2Ј,7Ј-dichlorodihydrofluorescein diacetate (CM-H 2 DCFDA) oxidation-based fluorescence assay], and this effect was partially reversed by the NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME). On the other hand, (6R)-5,6,7,8-tetrahydro-Lbiopterin (BH 4 ) normalized in part the ceramide-induced reduction in bioactive NO. Conclusions-Ceramide produces oxidative stress in human endothelial cells, thereby reducing bioactive NO. The partial reversal of this reduction by BH 4 and the diminution of ROS generation by L-NAME suggest that ceramide promotes NADPH oxidase activity of eNOS, leading to ROS formation at the expense of NO synthesis. The ceramide-induced upregulation of eNOS gene transcription can be considered an ineffective compensatory mechanism. The decreased bioavailability of NO is likely to favor a proatherogenic role of ceramide. (Circulation. 2002;106:2250-2256.)

Research paper thumbnail of The role of nitric oxide synthase in diabetes mellitus

Free Radical Biology and Medicine

Research paper thumbnail of Molecular Mechanisms on How Resveratrol Enhances Endothelial NO Production

https://www.novapublishers.com/catalog/product\_info.php?products\_id=34278

Research paper thumbnail of P378 RESVERATROL REVERSES eNOS UNCOUPLING: IMPLICATION OF SIRT1

Atherosclerosis Supplements, 2010

Research paper thumbnail of Anti-Inflammatory and Anti-Thrombotic Effects of the Fungal Metabolite Galiellalactone in Apolipoprotein E-Deficient Mice

PLOS ONE, 2015

Patients suffering from chronic inflammatory diseases have an increased mortality risk resulting ... more Patients suffering from chronic inflammatory diseases have an increased mortality risk resulting from cardiovascular disorders due to enhanced atherosclerotic and thrombotic events. Until now, it is not completely understood in which way an abnormal expression of pro-inflammatory mediators contributes to this elevated cardiovascular risk, but there is a need for new drugs that on the one hand suppress the expression of pro-inflammatory mediators and on the other hand inhibit arterial platelet adhesion. Thus, we analyzed the anti-inflammatory and anti-thrombotic capacity of the fungal metabolite Galiellalactone in atherosclerosis-prone apolipoprotein E-deficient mice. Treatment of the mice with Galiellalactone lowered the inflammatory expression profile and improved blood clotting times, as well as platelet adhesion to the injured common carotid artery. The results indicate that administration of Galiellalactone is able to reduce the extent of inflammation and arterial platelet adhesion in this mouse model.

Research paper thumbnail of Nebivolol Inhibits Superoxide Formation by NADPH Oxidase and Endothelial Dysfunction in Angiotensin II-Treated Rats

Nebivolol is a 1-receptor antagonist with vasodilator and antioxidant properties. Because the vas... more Nebivolol is a 1-receptor antagonist with vasodilator and antioxidant properties. Because the vascular NADPH oxidase is an important superoxide source, we studied the effect of nebivolol on endothelial function and NADPH oxidase activity and expression in the well-characterized model of angiotensin II-induced hypertension. Angiotensin II infusion (1 mg/kg per day for 7 days) caused endothelial dysfunction in male Wistar rats

Research paper thumbnail of Inhibitors of Histone Deacetylation Downregulate the Expression of Endothelial Nitric Oxide Synthase and Compromise Endothelial Cell Function in Vasorelaxation and Angiogenesis

Research paper thumbnail of Downregulation of BDNF Expression by PKC and by TNF-α in Human Endothelial Cells

Pharmacology, Jan 28, 2015

Brain-derived neurotrophic factor (BDNF) is a neurotrophin best characterized for its survival an... more Brain-derived neurotrophic factor (BDNF) is a neurotrophin best characterized for its survival and differentiative effects on neurons. Recent studies demonstrated that BDNF and its receptors are also expressed in the peripheral vasculature, where it stimulates angiogenesis and promotes the survival of endothelial cells. This study was designed to investigate the angiogenic effects of BDNF and its expressional regulation by tumor necrosis factor (TNF-α) and protein kinase C (PKC) in endothelial cells. In the Matrigel angiogenesis assay, BDNF-stimulated vascular tube formation of human umbilical vein endothelial cells (HUVEC) was completely blocked by an inhibition of the TrkB receptor, but only partially inhibited by the inhibition of the p75(NTR) signaling. Treatment of HUVEC and HUVEC-derived EA.hy 926 cells with TNF-α resulted in a downregulation of BDNF expression, which could be prevented by the TNFR1 antagonist WP9QY. BDNF downregulation by TNF-α was associated with decreased a...

Research paper thumbnail of NO Synthesis and NOS Regulation

Signal Transduction by Reactive Oxygen and Nitrogen Species: Pathways and Chemical Principles, 2004

Page 1. Chapter 7 NO SYNTHESIS AND NOS REGULATION Ulrich Forstermann, Huige Li, Petra M. Schwarz ... more Page 1. Chapter 7 NO SYNTHESIS AND NOS REGULATION Ulrich Forstermann, Huige Li, Petra M. Schwarz and Hartmut Kleinert 7.1 Introduction Nature has turned to nitric oxide (NO), a small bioactive gas, to mediate vital servoregulatory as well as cytotoxic functions. ...

Research paper thumbnail of Nitric Oxide: Biological Synthesis and Functions

Gasotransmitters: Physiology and Pathophysiology, 2012

ABSTRACT The pluripotent gaseous messenger molecule nitric oxide (NO) controls vital functions su... more ABSTRACT The pluripotent gaseous messenger molecule nitric oxide (NO) controls vital functions such as neurotransmission or vascular tone (via activation of soluble guanylyl cyclase), gene transcription, mRNA translation (via iron-responsive elements), and post-translational modifications of proteins (via ADP-ribosylation). In higher concentrations, NO is capable of destroying parasites and tumor cells by inhibiting iron-containing enzymes or directly interacting with the DNA of these cells. In view of this multitude of functions of NO, it is important to understand the mechanisms by which cells accomplish and regulate the production of this molecule. In mammals, three isozymes of NO synthase (NOS; L-arginine, NADPH:oxygen oxidoreductases, nitric oxide forming; EC 1.14.13.39) have been identified. These isoforms are referred to as neuronal “n”NOS (or NOS I), inducible “i”NOS (or NOS II), and endothelial “e”NOS (or NOS III). In pathophysiology, massive amounts of NO produced by hyperactive nNOS or highly expressed iNOS can contribute to processes such as neurodegeneration, inflammation, and tissue damage. This chapter will describe principles of NO biosynthesis, regulatory mechanisms controlling the production of this molecule, and the large array of (physiologic and pathophysiologic) functions that Mother Nature has assigned to this small messenger molecule.

Research paper thumbnail of Resveratrol as a gene regulator in the vasculature

Current pharmaceutical biotechnology, 2014

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) possesses multiple protective properties in th... more Resveratrol (3,5,4'-trihydroxy-trans-stilbene) possesses multiple protective properties in the vasculature, including anti-oxidative and anti-inflammatory effects and improvement of endothelial function. A substantial part of these effects is attributable to gene expression changes induced by the compound. Resveratrol can activate the NAD-dependent deacetylase sirtuin 1 (SIRT1), leading to deacetylation of SIRT1 target molecules such as NF-kB and forkhead box O (FOXO) transcription factors. The inhibition of NF-kB by resveratrol reduces the expression of inflammation mediators. FOXO factors are implicated in the upregulation of antioxidant enzymes and the endothelial-type nitric oxide synthase. In addition, resveratrol upregulates a number of antioxidant enzymes by activating nuclear factor-E2-related factor-2 (Nrf2) and downregulates NADPH oxidases through yet known mechanisms.

Research paper thumbnail of Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease

Arteriosclerosis, thrombosis, and vascular biology, 2014

Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory ski... more Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease. Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17A(ind/+) mice), associated with increased reactive oxygen species formation and circulating CD11b(+) inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls. In K14-IL-17A(ind/+) mice, immunohistochemistry and flow cytometry revealed increased vascular production of the nitric oxide/superoxide reaction product peroxynitrite and infiltration of the vasculature with myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) cells accompanied b...

Research paper thumbnail of Resveratrol and endothelial nitric oxide

Molecules (Basel, Switzerland), 2014

Nitric oxide (NO) derived from the endothelial NO synthase (eNOS) has antihypertensive, antithrom... more Nitric oxide (NO) derived from the endothelial NO synthase (eNOS) has antihypertensive, antithrombotic, anti-atherosclerotic and antiobesogenic properties. Resveratrol is a polyphenol phytoalexin with multiple cardiovascular and metabolic effects. Part of the beneficial effects of resveratrol are mediated by eNOS. Resveratrol stimulates NO production from eNOS by a number of mechanisms, including upregulation of eNOS expression, stimulation of eNOS enzymatic activity and reversal of eNOS uncoupling. In addition, by reducing oxidative stress, resveratrol prevents oxidative NO inactivation by superoxide thereby enhancing NO bioavailability. Molecular pathways underlying these effects of resveratrol involve SIRT1, AMPK, Nrf2 and estrogen receptors.

Research paper thumbnail of Dexamethasone upregulates Nox1 expression in vascular smooth muscle cells

Pharmacology, 2014

It has been demonstrated that dexamethasone-induced hypertension can be prevented by the NADPH ox... more It has been demonstrated that dexamethasone-induced hypertension can be prevented by the NADPH oxidase inhibitor apocynin. The effect of dexamethasone on NADPH oxidase, however, is unknown. The present study was conducted to investigate the effect of dexamethasone on the gene expression of Nox1, the major NADPH oxidase isoform in vascular smooth muscle cells. Oral treatment of Wistar-Kyoto rats with dexamethasone (0.03 mg/kg/day) for 12 days led to an upregulation of Nox1 mRNA expression in the aorta. In cultured A7r5 rat aortic smooth muscle cells, dexamethasone increased Nox1 mRNA expression in a concentration- and time-dependent manner. The upregulation of Nox1 mRNA expression was completely prevented by the glucocorticoid receptor antagonist mifepristone. The effect of dexamethasone on Nox1 expression was likely to be indirect as it could be largely blocked by cycloheximide, an inhibitor of protein biosynthesis. Dexamethasone increased Nox1 mRNA stability as well as Nox1 transcr...

Research paper thumbnail of Pharmacological prevention of eNOS uncoupling

Current pharmaceutical design, 2014

Under physiological conditions, nitric oxide (NO) is produced in the vasculature mainly by the en... more Under physiological conditions, nitric oxide (NO) is produced in the vasculature mainly by the endothelial NO synthase (eNOS). This endothelium-derived NO is a protective molecule with antihypertensive, antithrombotic and anti-atherosclerotic properties. Cardiovascular risk factors such as hypertension, hypercholesterolemia, cigarette smoking and diabetes mellitus induce oxidative stress mostly by stimulation of the NADPH oxidase. Overproduction of reactive oxygen species leads to oxidation of tetrahydrobiopterin (BH4), the essential cofactor of eNOS. In BH4 deficiency, oxygen reduction uncouples from NO synthesis, thereby converting eNOS to a superoxide- producing enzyme. Consequently, NO production is reduced and the pre-existing oxidative stress is enhanced, which contribute significantly to cardiovascular pathology. Therefore, pharmacological approaches that prevent eNOS uncoupling are of therapeutic interest. Among the drugs currently in clinical use, the renin inhibitor aliski...

Research paper thumbnail of Biphasic regulation of NADPH oxidase expression by protein kinase C in human endothelial cells

GBM Annual Spring meeting Mosbach 2006, 2006

Research paper thumbnail of Vascular oxidative stress, nitric oxide and atherosclerosis

Atherosclerosis, 2014

In the vascular wall, reactive oxygen species (ROS) are produced by several enzyme systems includ... more In the vascular wall, reactive oxygen species (ROS) are produced by several enzyme systems including NADPH oxidase, xanthine oxidase, uncoupled endothelial nitric oxide synthase (eNOS) and the mitochondrial electron transport chain. On the other hand, the vasculature is protected by antioxidant enzyme systems, including superoxide dismutases, catalase, glutathione peroxidases and paraoxonases, which detoxify ROS. Cardiovascular risk factors such as hypercholesterolemia, hypertension, and diabetes mellitus enhance ROS generation, resulting in oxidative stress. This leads to oxidative modification of lipoproteins and phospholipids, mechanisms that contribute to atherogenesis. In addition, oxidation of tetrahydrobiopterin may cause eNOS uncoupling and thus potentiation of oxidative stress and reduction of eNOS-derived NO, which is a protective principle in the vasculature. This review summarizes the latest advances in the role of ROS-producing enzymes, antioxidative enzymes as well as NO synthases in the initiation and development of atherosclerosis.

Research paper thumbnail of Role of nitric oxide synthase isoforms for ophthalmic artery reactivity in mice

Experimental Eye Research, 2014

Nitric oxide synthases (NOS) are involved in regulation of ocular vascular tone and blood flow. W... more Nitric oxide synthases (NOS) are involved in regulation of ocular vascular tone and blood flow. While endothelial NOS (eNOS) has recently been shown to mediate endothelium-dependent vasodilation in mouse retinal arterioles, the contribution of individual NOS isoforms to vascular responses is unknown in the retrobulbar vasculature. Moreover, it is unknown whether the lack of a single NOS isoform affects neuron survival in the retina. Thus, the goal of the present study was to examine the hypothesis that the lack of individual nitric oxide synthase (NOS) isoforms affects the reactivity of mouse ophthalmic arteries and neuron density in the retinal ganglion cell (RGC) layer. Mice deficient in one of the three NOS isoforms (nNOS-/-, iNOS-/- and eNOS-/-) were compared to respective wild type controls. Intraocular pressure (IOP) was measured in conscious mice using rebound tonometry. To examine the role of each NOS isoform for mediating vascular responses, ophthalmic arteries were studied in vitro using video microscopy. Neuron density in the RGC layer was calculated from retinal wholemounts stained with cresyl blue. IOP was similar in all NOS-deficient genotypes and respective wild type controls. In ophthalmic arteries, phenylephrine, nitroprusside and acetylcholine evoked concentration-dependent responses that did not differ between individual NOS-deficient genotypes and their respective controls. In all genotypes except eNOS-/- mice, vasodilation to acetylcholine was markedly reduced after incubation with L-NAME, a non-isoform-selective inhibitor of NOS. In contrast, pharmacological inhibition of nNOS and iNOS had no effect on acetylcholine-induced vasodilation in any of the mouse genotypes. Neuron density in the RGC layer was similar in all NOS-deficient genotypes and respective controls. Our findings suggest that eNOS contributes to endothelium-dependent dilation of murine ophthalmic arteries. However, the chronic lack of eNOS is functionally compensated by NOS-independent vasodilator mechanisms. The lack of a single NOS isoform does not appear to affect IOP or neuron density in the RGC layer.