Involvement of DDAH/ADMA/NOS pathway in nicotine-induced endothelial dysfunction

Jiang, De-Jian; Jia, Sujie; Yan, Jin; Zhou, Zhi; Yuan, Qiong; Li, Yuan‐Jian

doi:10.1016/j.bbrc.2006.08.115

Cited by 59 publications

(47 citation statements)

References 37 publications

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“…L-Arginine stimulates NO production in models of kidney disease (14), hypercholesterolemia, oxidative stress, inflammation, ischemia, and dietary salt restriction (31,66,77). However, a recent study in hepatic cells in vitro reports a dose-dependent inhibition of DDAH activity by L-arginine, which competes with ADMA for binding to DDAH (209), which should limit NO production.…”

Section: Sites Of Ddah Expression and Functionmentioning

confidence: 99%

“…Smokers have elevated plasma concentrations of ADMA and reduced eNOS expression (13,66,208), which correlate with elevated concentrations of homocysteine (208). Nicotine downregulates the mRNA and the protein expression of DDAH-2 and reduces DDAH activity in endothelial cells (66).…”

Section: Expression and Function Of Ddah In Diseasementioning

confidence: 99%

“…A recent study reports that endothelial cell dysfunction induced by nicotine is attenuated by the addition of L-arginine or by overexpression of DDAH-2 (66). Thus cigarette smoke, and/or the nicotine that it contains, could contribute to the endothelial dysfunction and cardiovascular disease of smokers by reducing DDAH-2 expression or function, thereby permitting the accumulation of ADMA that inhibits eNOS function and angiogenesis (66).…”

Section: Expression and Function Of Ddah In Diseasementioning

confidence: 99%

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Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Palm

Onozato²,

Luo³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

287

301

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Palm F, Onozato ML, Luo Z, Wilcox CS. Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol 293: H3227-H3245, 2007. First published October 12, 2007; doi:10.1152 doi:10. /ajpheart.00998.2007 )-dimethylarginine (ADMA) inhibits nitric oxide (NO) synthases (NOS). ADMA is a risk factor for endothelial dysfunction, cardiovascular mortality, and progression of chronic kidney disease. Two isoforms of dimethylarginine dimethylaminohydrolase (DDAH) metabolize ADMA. DDAH-1 is the predominant isoform in the proximal tubules of the kidney and in the liver. These organs extract ADMA from the circulation. DDAH-2 is the predominant isoform in the vasculature, where it is found in endothelial cells adjacent to the cell membrane and in intracellular vesicles and in vascular smooth muscle cells among the myofibrils and the nuclear envelope. In vivo gene silencing of DDAH-1 in the rat and DDAH ϩ/Ϫ mice both have increased circulating ADMA, whereas gene silencing of DDAH-2 reduces vascular NO generation and endothelium-derived relaxation factor responses. DDAH-2 also is expressed in the kidney in the macula densa and distal nephron. Angiotensin type 1 receptor activation in kidneys reduces the expression of DDAH-1 but increases the expression of DDAH-2. This rapidly evolving evidence of isoform-specific distribution and regulation of DDAH expression in the kidney and blood vessels provides potential mechanisms for nephron site-specific regulation of NO production. In this review, the recent advances in the regulation and function of DDAH enzymes, their roles in the regulation of NO generation, and their possible contribution to endothelial dysfunction in patients with cardiovascular and kidney diseases are discussed. nitric oxide synthase; hypertension; diabetes mellitus; chronic kidney disease; asymmetric dimethylarginineis an endogenous methylated amino acid that inhibits the constitutive endothelial (e) or type III and neuronal (n) or type I isoforms of nitric oxide (NO) synthase (NOS) (49,91,103,199). It is a less potent inhibitor of the inducible (i) or type II NOS isoform (41,191,213). Proteins are subject to methylation of arginine residues by protein arginine methyltransferase (PRMT). S-adenosylmethionine, which is synthesized from methionine and ATP, serves as the methyl donor and, in the process, is converted to S-adenosylhomocysteine, which itself can be hydrolyzed to homocysteine. Remethylation of homocysteine in the "remethylation pathway" regenerates methionine (14,179). ADMA is released by protein hydrolysis and exported from the cell and taken up by other cells via system y ϩ carriers of the cationic amino acid (CAT) family (14,196,212). ADMA is eliminated both by renal excretion and metabolic degradation. Its metabolism is facilitated by dimethylarginine dimethylaminohydrolases (DDAHs), which are expressed as type 1 and 2 isoforms. Recent studies have shown differential sites of expression of DDAH-1 and -2 in blo...

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Section: Sites Of Ddah Expression and Functionmentioning

confidence: 99%

Section: Expression and Function Of Ddah In Diseasementioning

confidence: 99%

Section: Expression and Function Of Ddah In Diseasementioning

confidence: 99%

See 1 more Smart Citation

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Palm

Onozato²,

Luo³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

287

301

View full text Add to dashboard Cite

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“…9 It has been reported that either decreased expression of DDAH or reduced activity of DDAH is responsible for the elevation of ADMA. 10,11 Given its pharmacological function as a modulator of NO activity, and the relationship with endothelial dysfunction, it is likely that ADMA is associated with the pathogenesis of ED. Several lines of evidence have suggested the potential relationship between ADMA and ED, especially in patients with CADs.…”

Section: Introductionmentioning

confidence: 99%

Dimethylarginine dimethylaminohydrolase in rat penile tissue: reduced enzyme activity is responsible for erectile dysfunction in a rat model of atherosclerosis

Park¹,

Lee²,

et al. 2009

Int J Impot Res

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Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is mainly metabolized by N G ,N G -dimethylarginine dimethylaminohydrolase (DDAH). We investigated whether altered cavernosal ADMA-DDAH metabolism might cause impairment of erection in rat model of atherosclerosis (AS). Male Sprague-Dawley rats (3 months old) were divided into an AS group and a normal control (Con) group (n ¼ 20 in each group). The AS rats received AS-prone treatment (6 weeks of 1% cholesterol diet plus early 2 weeks of N G -nitro-L-arginine methyl ester (3 mg ml À1 per day) treatment). After 6 weeks, rats underwent cavernosometry measuring the maximal intracavernosal pressure/mean arterial pressure (ICP/MAP) ratios as a surrogate marker of erectile function. The amount of cavernosal ADMA was assessed by immunoblot analysis and correlated with the ICP/MAP. Isoform-specific DDAH expression was compared by immunohistochemistry. Cavernosal DDAH and NOS activity were measured. Cavernosal malondialdehyde levels were assayed to determine the degree of lipid peroxidation. Compared to the controls, the AS rats had signs of impaired erectile function. Higher cavernosal ADMA was observed in the AS rats. The cavernosal ADMA had a moderately negative correlation with the ICP/MAP. Immunohistochemistry revealed the expression of both isoforms was not affected by the presence of AS. However, significantly diminished DDAH as well as NOS activity was observed in the AS group. In addition, elevated cavernosal malondialdehyde levels were noted in the AS rats. Our study showed that decreased cavernosal DDAH activity is the cause of cavernosal ADMA accumulation leading to reduced cavernosal NOS activity and impairment of erectile function.

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“…NO bioavailability is decreased in cigarette smokers (16,17), but the underlying mechanism was not clarified. Physiological and pharmacological effects of nicotine, a major component of cigarette smoke, are well established, and it is reported that treatment with nicotine impairs endothelial function by decreasing NO bioavailability in the experimental animals (18,19). Cigarette smoke contains numerous vasoconstricting and vasorelaxing components other than nicotine (20, 21), and cigarette smoke extract (CSE) exposure affects vasomotor responses of isolated arteries (22,23).…”

Section: Introductionmentioning

confidence: 99%

Chronic Administration of Nicotine-Free Cigarette Smoke Extract Impaired Endothelium-Dependent Vascular Relaxation in Rats via Increased Vascular Oxidative Stress

et al. 2012

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CorrigendumCorrigendum to "Chronic administration of nicotine-free cigarette smoke extract impaired endothelium-dependent vascular relaxation in rats via increased vascular oxidative stress" [J Pharmacol Sci 118 (2012) 206Journal of Pharmacological Sciences © The Japanese Pharmacological Society J Pharmacol Sci 118, 206 -214 (2012) IntroductionEpidemiological studies indicate that cigarette smoking is one of the independent risk factors for hypertension, atherosclerosis, and ischemic heart diseases (1 -4). Endothelial dysfunction is thought to be an early sign of atherosclerosis (5) and that is observed in rodent models of cardiovascular diseases (6 -8). Impairment of vascular endothelial function has been reported in chronic smokers (9 -11). Nitric oxide (NO) is an intercellular signal-mediating molecule in the cardiovascular, immune, and nervous systems (12). In the cardiovascular system, NO plays a crucial role in the regulation of vascular tone (13,14) and in protecting against the development of atherosclerosis (15). NO bioavailability is decreased in cigarette smokers (16,17), but the underlying mechanism was not clarified. Physiological and pharmacological effects of nicotine, a major component of cigarette smoke, are well established, and it is reported that treatment with nicotine impairs endothelial function by decreasing NO bioavailability in the experimental animals (18,19). Cigarette smoke contains numerous vasoconstricting and vasorelaxing components other than nicotine (20, 21), and cigarette smoke extract (CSE) exposure affects vasomotor responses of isolated arteries (22,23). Recently nicotine-free CSE has attracted attention in the pathogenesis of vascular disorders caused by smoking (24 -26). However, the effect of cigarette smoke components other than nicotine on regulation of cardiovascular function is not sufficiently examined. Therefore, in the present study, acute and chronic effects of nicotine-free CSE on the vascular responsiveness were Science, Seta, Otsu, Shiga 520-2192, Japan Received October 7, 2011 Accepted December 12, 2011 Abstract. Cigarette smoking has been implicated in the initiation and progression of cardiovascular disorders and atherosclerosis. Here, we examined the effects of nicotine-free cigarette smoke extract (CSE) on the regulation of cardiovascular function. Rats were subcutaneously administered PBS or nicotine-free CSE at 0.05 to 1.5 mL/day per rat for 4 weeks. Blood pressure, cardiac function, and vascular responsiveness were measured at 4 weeks after administration. Furthermore, acute effects of nicotine-free CSE were also studied in the aorta isolated from normal rats. Blood pressure and left ventricular systolic pressure (LVSP) were significantly increased in the nicotinefree CSE-administered rats, but heart rate, dP/dt max , and dP/dt min were not affected. Endotheliumdependent relaxation by acetylcholine (ACh) in the nicotine-free CSE-treated rats was significantly attenuated compared to PBS-treated rats, but endothelium-independent relaxation ...

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Involvement of DDAH/ADMA/NOS pathway in nicotine-induced endothelial dysfunction

Cited by 59 publications

References 37 publications

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Dimethylarginine dimethylaminohydrolase in rat penile tissue: reduced enzyme activity is responsible for erectile dysfunction in a rat model of atherosclerosis

Chronic Administration of Nicotine-Free Cigarette Smoke Extract Impaired Endothelium-Dependent Vascular Relaxation in Rats via Increased Vascular Oxidative Stress

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