Taurine protects against low-density lipoprotein-induced endothelial dysfunction by the DDAH/ADMA pathway

Asymmetric dimethylarginine (ADMA), a major endogenous nitric oxide (NO) synthase inhibitor, is thought to be a key contributor for endothelial dysfunction. Decrease in activity of dimethylarginine dimethylaminohydrolase (DDAH), a major hydrolase of ADMA, causes accumulation of ADMA in some risk factors of atherosclerosis, including hypercholesterolemia. Taurine is a semi-essential amino acid that has previously been shown to have endothelial protective effects. The present study was to test whether the protective effect of taurine on endothelial function is related to modulation of the DDAH/ADMA pathway. A single injection of native LDL (4 mg/kg, i.v.) markedly reduced endothelium-dependent vasorelaxation and the plasma level of NO, and increased plasma concentrations of ADMA, malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-alpha). Treatment with taurine in vivo (60 or 180 mg/kg) significantly attenuated the inhibition of endothelium-dependent vasorelaxation and the reduced level of NO, and decreased the elevated levels of ADMA, MDA, and TNF-alpha. Incubation human umbilical vein endothelial cells (HUVECs) with ox-LDL (100 microg/ml) for 24 h markedly increased the medium levels of lactate dehydrogenase (LDH), ADMA, TNF-alpha and MDA, and decreased the level of NO in the medium and the intracellular activity of DDAH. Taurine (1 or 5 microg/ml) significantly attenuated the increases in the levels of LDH, ADMA, TNF-alpha and MDA, and the decrease in the level of NO and the activity of DDAH induced by ox-LDL in HUVECs. The present results suggested that taurine protected against endothelial dysfunction induced by native LDL in vivo or by ox-LDL in endothelial cells, and the protective effect of taurine on the endothelium is related to decrease in ADMA level by increasing of DDAH activity.     

Demethylbellidifolin inhibits adhesion of monocytes to endothelial cells via reduction of tumor necrosis factor alpha and endogenous nitric oxide synthase inhibitor level

The effect of demethylbellidifolin (DMB), a major compound of Swertia davidi Franch, on the adhesion of monocytes to endothelial cells induced by oxidized low-density lipoprotein (ox-LDL) was studied. Adhesion of monocytes to endothelial cells was induced by treatment with ox-LDL (100 microg/mL) for 48 h. Levels of tumor necrosis factor-alpha (TNF-alpha) and asymmetric dimethylarginine (ADMA, an endogenous inhibitor of NOS) in conditioned medium and the activity of dimethylarginine dimethylaminohydrolase (DDAH) in endothelial cells were measured. DMB (3 or 10 micromol/L) significantly inhibited the adhesion of monocytes to endothelial cells, attenuated an increase in levels of TNF-alpha and ADMA, and a decrease in the activity of DDAH by ox-LDL. The present results suggest that DMB inhibits the increased adhesion of monocytes to endothelial cells induced by ox-LDL, and that the effect of DMB is related to reduction of the ADMA concentration via reduction of TNF-alpha production in cultured endothelial cells treated with ox-LDL.     

Aspirin protected against endothelial damage induced by LDL： role of endogenous NO synthase inhibitors in rats

AIM: To study the protective effect of aspirin on damages of the endothelium induced by low-density lipoprotein (LDL), and whether the protective effect of aspirin is related to reduction of nitric oxide synthase inhibitor level.METHODS: Vascular endothelial injury was induced by a single injection of native LDL (4 mg/kg) in rats. Vasodilator responses to acetylcholine (ACh) in the isolated aortic rings were determined, and serum concentrations ofasymmetric dimethylarginine (ADMA), malondialdehyde (MDA), tumour necrosis factor-α (TNF-α), and the activity of dimethylaminohydrolase (DDAH) were measured. RESULTS: A single injection of LDL (4 mg/kg)significantly decreased vasodilator responses to ACh, increased the serum level of ADMA, MDA, and TNF-α, anddecreased DDAH activity. Aspirin (30 or 100 mg/kg) markedly reduced the inhibition of vasodilator responses toACh by LDL, and the protective effect of aspirin at the lower dose was greater compared with high-dose aspiringroup. Aspirin inhibited the increased level of MDA and TNF-α induced by LDL. Aspirin at the dose of 30 mg/kg,but not at higher dose (100 mg/kg), significantly reduced the concentration of ADMA and increased the activity ofDDAH. CONCLUSION: Aspirin at the lower dose (30 mg/kg) protects the endothelium against damages elicitedby LDL in vivo, and the protective effect of aspirin on endothelium is related to reduction of ADMA concentrationby increasing DDAH activity.     

Protective effects of daviditin A against endothelial damage induced by lysophosphatidylcholine

Previous investigations have indicated that endogenous inhibitors of nitric oxide synthase (NOS) such as asymmetric dimethylarginine (ADMA) may play an important role in endothelium dysfunction, and some antioxidant drugs improve endothelium function via reduction of ADMA level. The present study examined the antioxidation and endothelial protection of daviditin A, a xanthone compound. Daviditin A significantly inhibited Cu(2+)-induced low-density lipoprotein (LDL) oxidation (EC50: 38.7 microM) and scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals (EC50: 57.5 microM). Vasodilator responses to acetylcholine in rings of the isolated thoracic aorta were impaired in the presence of lysophosphatidylcholine (LPC)(5 mg/l). Daviditin A (10 or 30 microM) significantly attenuated inhibition by LPC of endothelium-dependent relaxation. Incubation of ECV304 cells with LPC (5 mg/l) for 24 h markedly elevated lactate dehydrogenase (LDH) activity and the levels of malondialdehyde (MDA) and ADMA, and decreased the content of nitric oxide (NO) and the activity of dimethylarginine dimethylaminohydrolase (DDAH). Daviditin A (1, 3 or 10 microM) significantly attenuated the increased release of LDH, increased content of MDA, and decreased level of NO induced by LPC. Daviditin A (3 or 10 microM) significantly inhibited the increased concentration of ADMA. Daviditin A (10 microM) significantly attenuated the decreased activity of DDAH. The present results suggest that daviditin A preserves endothelial dysfunction elicited by LPC, and the protective effect of daviditin A on the endothelium is related to reduction of ADMA concentration.     

Lysophosphatidylcholine-induced elevation of asymmetric dimethylarginine level by the NADPH oxidase pathway in endothelial cells

Recent studies suggested that endothelium is a main source of reactive oxygen species (ROS) and the major source was via NADPH oxidase pathway. Various stimuli including lysophosphatidylcholine (LPC), a major component of oxidized low-density lipoprotein (ox-LDL), can enhance the activity of NADPH oxidase and lead to a marked ROS generation. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthase (NOS) inhibitor, which is synthesized by protein arginine methyltransferase I (PRMT I) and degraded by dimethylarginine dimethylaminohydrolase (DDAH) in endothelial cells. Much evidence showed that ADMA was closely related to endothelial dysfunction. Our previous study showed that LPC elevated ADMA level in endothelial cells via increasing oxidative stress, but the precise cellular mechanism is not defined yet. The present study was to explore the mechanism of NADPH oxidase in LPC-induced elevation of ADMA. In LPC-treated endothelial cells, the ROS production, cell viability, ADMA and NO levels, the activity of DDAH and expression of PRMT I were detected. Treatment with LPC (10 microg/ml) for 24 h markedly increased intracellular ROS production, the expression of PRMT I, level of ADMA, decreased the concentration of NO and the activity of DDAH. These effects were attenuated by diphenyliodonium, the NADPH oxidase inhibitor. In summary, the present results suggested that LPC-induced elevation of ADMA was due to reduction of DDAH activity and the up-regulation of PRMT expression by stimulation of ROS production via NADPH oxidase pathway.     

Probucol preserves endothelial function by reduction of the endogenous nitric oxide synthase inhibitor level

1. Oxide low-density lipoprotein (ox-LDL) is believed to play an important role in early events of atherogenesis, and asymmetric dimethylarginine (ADMA) is associated with the development of endothelial dysfunction. The present study examined the effect of a single injection of native low-density lipoprotein (LDL) on endothelium function and the serum level of ADMA and the effect of probucol on endothelium function and ADMA level in rats. 2. Endothelial injury was induced by intravenous injection of LDL at the dose of 2, 4, or 6 mg kg(-1) for 24, 48, or 72 h, and vasodilator responses to acetylcholine in the aortic rings and serum levels of ADMA, nitrite/nitrate (NO) and malondialdehyde (MDA) were determined. 3. Pretreatment with LDL markedly reduced endothelium-dependent relaxation in a concentration-dependent manner. Inhibition of vasodilator responses to acetylcholine by LDL was abolished in the presence of L-arginine (3 x 10(-4) M). Serum levels of ADMA and MDA were significantly elevated in the rats pretreated with LDL, while serum level of nitrite/nitrate was markedly decreased. 4. Pretreatment with probucol significantly improved endothelium-dependent relaxation, decreased concentrations of ADMA and MDA and increased nitrite/nitrate level in the rats treated with LDL. A similar effect was seen in the rats pretreated with an antioxidant vitamin E. 5. These results suggest that a single injection of native LDL causes endothelial dysfunction by elevation of ADMA levels and that the protective effect of probucol on endothelial cells is related to reduction of ADMA concentration.     

Involvement of asymmetric dimethylarginine and Rho kinase in the vascular remodeling in monocrotaline-induced pulmonary hypertension

Recent studies have shown that the plasma level of asymmetric dimethylarginine (ADMA) was increased accompanied by the decreased dimethylarginine dimethylaminohydrolase (DDAH) activity in pulmonary hypertension (PH) and ADMA was able to regulate pulmonary endothelial cells mobility through increasing the activity of Rho kinase (ROCK). This work was conducted to explore the role of ADMA/DDAH pathway in vascular remodeling in PH and the underlying mechanisms. The rat model of PH was established by a single injection of monocrotaline (60 mg/kg, s.c.). The pulmonary arterial pressure, the remodeling of pulmonary artery, the hypertrophy of right ventricle, the plasma levels of ADMA and NO, the expression of DDAH2, ROCK1 or ROCK2 and the ROCK activity were determined. In vitro studies, the pulmonary artery smooth muscle cells (PASMCs) were isolated and cultured. The effect of ADMA on PASMCs proliferation and ROCK activation was investigated. The results showed that the injection of monocrotaline successfully induced PH characterized by the increased pulmonary arterial pressure, vascular remodeling and right ventricle hypertrophy. The plasma level of ADMA was elevated concomitantly with the increased ROCK activity and ROCK1 expression as well as the decreased DDAH2 expression in pulmonary arteries. In the cultured PASMCs, ADMA promoted cellular proliferation accompanied by the increased ROCK1 expression and ROCK activity, which was attenuated by the ROCK inhibitor or by the intracellular antioxidant. These results suggest that ADMA could promote the proliferation of PASMCs through activating ROCK pathway, which may account for, at least partially, the vascular remodeling in monocrotaline-induced PH.     

Role of asymmetric dimethylarginine (ADMA) in diabetic vascular complications

Nitric oxide (NO) is a well-recognized anti-atherogenic factor; it inhibits the inflammatory-proliferative processes in atherosclerosis. Indeed, endothelial dysfunction due to reduced synthesis and/or bioavailability of NO is thought to be an early step in the course of atherosclerotic cardiovascular disease (CVD). NO is synthesized from L-arginine via the action of NO synthase (NOS), which is known to be blocked by endogenous L-arginine analogues such as asymmetric dimethylarginine (ADMA), a naturally occurring amino acid found in plasma and various types of tissues. Recently, it has been demonstrated that plasma levels of ADMA are elevated in patients with diabetes. These findings suggest that the elevated ADMA in diabetes could contribute to acceleration atherosclerosis in this population. Further, since ADMA is mainly metabolized by dimethylarginine dimethylaminohydrolase (DDAH), it is conceivable that the inhibition of ADMA via up-regulation of DDAH may be a novel therapeutic target for the prevention of CVD in patients with diabetes. In this paper, we review the pathophysiological role of ADMA and DDAH system for accelerated atherosclerosis in diabetes and the therapeutic utility of ADMA suppression in CVD in diabetes.     

The biology and therapeutic potential of the DDAH/ADMA pathway

Asymmetric dimethylarginine (ADMA) is an endogenously produced molecule that inhibits nitric oxide synthase and consequently may have adverse effects on physiology, in particular in the cardiovascular system. This review highlights the mechanisms involved in the synthesis and metabolism of ADMA and their role in the control of nitric oxide (NO) synthesis. We describe how the effects of both cellular and circulating ADMA can alter physiological function involving both NO dependent and independent pathways and go on to describe how the metabolism of ADMA by dimethylarginine dimethylaminohydrolase (DDAH) is the major endogenous mechanism by which ADMA levels are regulated. Furthermore, we discuss the association of ADMA concentrations with cardiovascular disease and how ADMA levels can be modulated therapeutically by altering its production and/or metabolism. Finally we discuss the effects of some of the current pharmaceutical therapies used to treat cardiovascular disease and their involvement in the modulation of the ADMA/DDAH pathway.     

Nebivolol reduces asymmetric dimethylarginine in endothelial cells by increasing dimethylarginine dimethylaminohydrolase 2 (DDAH2) expression and activity

Asymmetric dimethylarginine (ADMA) has been reported to affect the synthesis of nitric oxide (NO) in endothelial cells by inhibiting endothelial NO synthase (eNOS) activity and to cause endothelial dysfunction in humans. This study was conducted in human umbilical vein endothelial cells (HUVECs) to evaluate the effect of nebivolol, a selective beta1-adrenergic receptor antagonist, on ADMA concentration and on dimethylarginine dimethylaminohydrolase (DDAH2), the enzyme that regulates ADMA catabolism. Nebivolol dose-dependently decreased ADMA/symmetric dimethylarginine (SDMA) ratio (p from <0.01 to <0.001). This was parallelled by a dose-dependent increase in DDAH2 mRNA (p from <0.01 to <0.001) and protein expression (p from <0.01 to <0.001) and activity (p from <0.01 to <0.001). The small interference RNA (siRNA)-mediated knockdown of DDAH2 abolished the modification of DDAH2 expression (p<0.001) and ADMA/SDMA ratio (p<0.001) induced by nebivolol. In conclusion, the results of this study demonstrate that nebivolol reduces ADMA concentration by increasing DDAH2 expression and activity. Our in vitro findings describe a novel vascular effect of nebivolol and clearly identify this compound as the first antihypertensive agent that modulates DDAH2 in endothelial cells.     

Mechanisms of nitric oxide synthase uncoupling in endotoxin-induced acute lung injury: Role of asymmetric dimethylarginine

Acute lung injury (ALI) is associated with severe alterations in lung structure and function and is characterized by hypoxemia, pulmonary edema, low lung compliance and widespread capillary leakage. Asymmetric dimethylarginine (ADMA), a known cardiovascular risk factor, has been linked to endothelial dysfunction and the pathogenesis of a number of cardiovascular diseases. However, the role of ADMA in the pathogenesis of ALI is less clear. ADMA is metabolized via hydrolytic degradation to l-citrulline and dimethylamine by the enzyme, dimethylarginine dimethylaminohydrolase (DDAH). Recent studies suggest that lipopolysaccharide (LPS) markedly increases the level of ADMA and decreases DDAH activity in endothelial cells. Thus, the purpose of this study was to determine if alterations in the ADMA/DDAH pathway contribute to the development of ALI initiated by LPS-exposure in mice. Our data demonstrate that LPS exposure significantly increases ADMA levels and this correlates with a decrease in DDAH activity but not protein levels of either DDAH I or DDAH II isoforms. Further, we found that the increase in ADMA levels cause an early decrease in nitric oxide (NO_x) and a significant increase in both NO synthase (NOS)-derived superoxide and total nitrated lung proteins. Finally, we found that decreasing peroxynitrite levels with either uric acid or Manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTymPyp) significantly attenuated the lung leak associated with LPS-exposure in mice suggesting a key role for protein nitration in the progression of ALI. In conclusion, this is the first study that suggests a role of the ADMA/DDAH pathway during the development of ALI in mice and that ADMA may be a novel therapeutic biomarker to ascertain the risk for development of ALI.     

Calycosin and formononetin from astragalus root enhance dimethylarginine dimethylaminohydrolase 2 and nitric oxide synthase expressions in Madin Darby Canine Kidney II cells

Nitric oxide (NO) is a crucial vasodilator produced by nitric oxide synthase (NOS). Asymmetric dimethylarginine (ADMA) is an endogenous NOS inhibitor and mainly catabolized by dimethylarginine dimethylaminohydrolase (DDAH). As we reported, the antihypertensive effect of shichimotsukokato (SKT), a formula of Japanese traditional kampo medicine consisting of 7 crude drugs, in 5/6 nephrectomized rats, is mediated by the DDAH-ADMA-NO pathway. Our present study aimed to explore the effective compounds of SKT using Madin Darby Canine Kidney (MDCK) II cells. We isolated two isoflavones, calycosin and formononetin from astragalus root, one of the components of SKT, which can promote DDAH2 protein and mRNA expressions in MDCK II cells. The neuronal NOS levels were also upregulated by the treatment of calycosin and formononetin. These results suggest that calycosin and formononetin could be the active ingredients of astragalus root and SKT that cause antihypertensive effects. The increased levels of DDAH2 and NOS may enhance NO production, decrease ADMA level and improve endothelial and cardiovascular dysfunction.     

Fenofibrate decreases asymmetric dimethylarginine level in cultured endothelial cells by inhibiting NF-κB activity

Previous investigations have demonstrated that endogenous inhibitors of nitric oxide synthase (NOS), such as asymmetric dimethylarginine (ADMA), contribute importantly to endothelial dysfunction, and that fenofibrate has a protective effect on the endothelium in rats treated with low-density lipoprotein (LDL) by reducing ADMA levels. In the present study, we explored further the possible mechanism underlying inhibition of ADMA generation by fenofibrate in cultured human umbilical vein endothelial cells (HUVECs). Endothelial injury was induced in cultured HUVECs by incubation with oxidative LDL (ox-LDL) and the levels of ADMA, lactate dehydrogenase (LDH), NO and tumour necrosis factor- (TNF-) in the conditioned medium were measured. Cell viability and the activity of dimethylarginine dimethylaminohydrolase (DDAH) and nuclear factor-B (NF-B) in the cultured HUVECs were also determined. Incubation of HUVECs with ox-LDL (100 g/ml) for 24 h markedly elevated ADMA, LDH and TNF- in the conditioned medium and significantly increased the activity of NF-B, concomitantly with a significant decrease in the activity of DDAH and the content of NO. Pretreatment with fenofibrate (3, 10 or 30 M) significantly inhibited the increases in ADMA, LDH and TNF-, attenuated the decreased levels of NO and the decreased activity of DDAH and prevented the activation of NF-B. Similar effects were observed in the presence of pyrrolidine dithiocarbamate (PDTC, 10 M), an antagonist of NF-B. The beneficial effects of fenofibrate on cultured endothelial cells were abolished by MK-886, a specific peroxisome proliferator-activated receptor- (PPAR) antagonist. The present results suggest that fenofibrate inhibits ox-LDL-induced endothelial cell damage by decreasing ADMA and increasing DDAH activity, and the protective effects of fenofibrate on endothelial cells may be related to reduction of NF-B activity by activation of the PPAR receptor.     

Asymmetric dimethylarginine (ADMA) as a target for pharmacotherapy

Asymmetric dimethylarginine (ADMA) is synthesized during the methylation of protein arginine residues by protein arginine methyltransferases (PRMT) and is released during proteolysis. ADMA is a competitive inhibitor of nitric oxide synthase and may decrease NO availability. ADMA is eliminated by renal excretion or is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to citruline and dimethylamine. Two other endogenous methylarginines are also synthesized by PRMT: N-monomethyl-L-arginine (L-NMMA) and symmetric dimethylarginine (SDMA). L-NMMA inhibits NO synthase but its concentrations in circulation are much lower than ADMA whereas SDMA is inactive. Plasma concentration of ADMA is markedly increased in patients with chronic renal failure and moderately increased in patients with many other diseases including hyperlipidemia, diabetes mellitus, arterial hypertension, hyperhomocysteinemia and heart failure. The increased concentration of ADMA is positively correlated with markers of atherosclerosis, such as carotid artery intima-media thickness and has a predictive value for acute cardiovascular events in prospective studies. Angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor antagonists, vitamin E and, according to some studies, estrogens used in hormonal replacement therapy reduce plasma ADMA concentration, which may contribute to their beneficial effect on NO synthesis and endothelial function. However, in some states associated with excess of NO, such as septic shock or excitotoxic neuronal injury ADMA may be protective by limiting toxic effect of high concentrations of NO. This article reviews the effect of pharmacotherapy on ADMA metabolism and its possible clinical implications.     

桂哌齐特拮抗氧化低密度脂蛋白对人脐静脉内皮细胞的损伤

目的研究桂哌齐特对氧化低密度脂蛋白(ox-LDL)损伤人脐静脉内皮细胞系ECV304的保护作用。方法传代培养ECV304细胞,随机分为空白对照组、模型组、桂哌齐特(200mg·L~(-1)和400mg·L~(-1))组,与ox-LDL共同孵育24h制模,观察培养上清液中一氧化氮(NO)与丙二醛(MDA)含量的变化,测定Fura-2/AM负载后的内皮细胞的游离静息钙浓度([Ca~(2+)]_i)。结果 ox-LDL诱导的模型组上清液中NO的浓度明显降低,MDA含量显著升高(均P<0.01)。桂哌齐特组NO浓度增加(P<0.01),MDA含量降低均(P<0.05)。与空白对照组相比,模型组的[Ca~(2+)]_i显著升高,桂哌齐特组能降低损伤导致的[Ca~(2+)]_i升高(均P<0.01)。结论桂哌齐特能拮抗ox-LDL对人脐静脉内皮细胞的损伤作用。     

金雀异黄素对低密度脂蛋白诱导的内皮细胞c-myc mRNA表达的影响(英文)

目的 :研究金雀异黄素对氧化型低密度脂蛋白诱导的人血管内皮细胞c mycmRNA表达的影响。方法 :低密度脂蛋白采用密度梯度超速离心法从健康人血浆中提取 ,经铜离子氧化制备成氧化型低密度脂蛋白。培养的人血管内皮细胞给予氧化型低密度脂蛋白 2 0 0mg·L- 1或同时给予金雀异黄素 10 0 μmol·L- 1诱导不同时间 (1,2 ,4h) ,提取细胞总RNA进行Northernblot杂交。结果 :2 0 0mg·L- 1氧化型低密度脂蛋白刺激内皮细胞c mycmR NA在 1h增加为对照水平的 3倍 ,2h增加为对照水平的 3.3倍 ,4h降到对照水平以下 ;给予氧化型低密度脂蛋白诱导的同时给予金雀异黄素 10 0 μmol·L- 1其c mycmRNA表达量在 1h为单独给予氧化型低密度脂蛋白诱导的 80 % ,2h为 6 0 %。结论 :金雀异黄素能有效抑制氧化型低密度脂蛋白诱导的人血管内皮细胞c mycmRNA表达增高     

二甲基精氨酸二甲胺水解酶与心血管疾病

二甲基精氨酸二甲胺水解酶(DDAH)是一种胞浆蛋白酶,包括DDAH1和DDAH2两种亚型,能特异性水解内源性一氧化氮合酶(NOS)抑制物非对称二甲基精氨酸而上调NOS活性。DDAH与NOS活性之间的相互作用在调节NO生成和血管内皮功能中起重要作用。DDAH还参与血管新生与细胞分化的调节,其活性变化与动脉粥样硬化等多种心血管疾病的发生发展密切相关,可能是一个新的心血管疾病相关蛋白和药物防治靶点。     

Asymmetric dimethylarginine induces TNF-alpha production via ROS/NF-kappaB dependent pathway in human monocytic cells and the inhibitory effect of reinioside C

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, has been implicated in vascular inflammation through induction of reactive oxygen species (ROS) and proinflammatory genes in endothelial cells. However, relatively few attentions have been paid to the effect of ADMA on monocytes, one of the important cells throughout all stages of atherosclerosis. In the present study, we found that reinioside C, the main component extracted from Polygala fallax Hemsl., dose-dependently inhibited tumor necrosis factor-alpha (TNF-alpha) production induced by ADMA in monocytes, Furthermore, reinioside C attenuated ADMA-induced generation of reactive oxygen species and activation of nuclear factor-kappaB (NF-kappaB) activity in monocytes in a dose-dependent manner, this effect was inhibited by l-arginine (NOS substrate) and PDTC (inhibitor of NF-kappaB). These data suggest that reinioside C could attenuate the increase of TNF-alpha induced by exogenous ADMA through inhibition ROS/NF-kappaB pathway in monocytes.     

ADMA and the role of the genes: Lessons from genetically modified animals and human gene polymorphisms

In large population-based cohorts, elevated plasma levels of asymmetric dimethylarginine (ADMA) were found to be associated with cardiovascular events and mortality. Impairment of nitric oxide (NO) synthesis from l-arginine has been postulated as underlying mechanism.In the present review, we compare different experimental models of NOS deficiency or overexpression with corresponding models of altered metabolism of ADMA by dimethylarginine dimethylaminohydrolase (DDAH). The latter models show a considerable overlap with the pathophysiological features of impaired NO synthesis, such as impaired endothelial function, elevation of blood pressure, and microvascular fibrosis. In line with these findings, first data regarding genetic variation of DDAH-metabolism in humans are reminiscent of the (rather modest) effects previously observed with polymorphisms of the eNOS gene. However, several peculiar observations suggest that ADMA- or DDAH-related pathology may extend beyond impairment of NO-mediated signalling. Notably, the complete knock out of DDAH1 appears to be lethal while triple NOS^−/− mice are viable. Moreover, some ADMA-mediated pathology appears to respond rather to ACE-inhibition than to l-arginine. Here, a further investigation of alternative target enzymes for ADMA and other endogenous DDAH substrates is warranted.Taken together, the current data suggest that ADMA-related pathology can largely but not completely be explained by impaired NO metabolism.