Identification of a Novel Polymorphism in the 3′UTR of the
            <scp>l</scp>
            -Arginine Transporter Gene
            <i>SLC7A1</i>

Yang, Zhaohuai; Venardos, Kylie; Jones, Emma; Morris, Brian J.; Chin-Dusting, Jaye; Kaye, David M.

doi:10.1161/circulationaha.106.665836

Cited by 74 publications

(69 citation statements)

References 26 publications

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“…We recently demonstrated that superoxide dismutase inhibition augmented oxidative stress and increased arterial pressure in mice. 50 Of note, we found that transgenic mice with augmented endothelial-specific l-arginine transport 51 were resistant to the development of superoxide dismutase inhibition-induced oxidative stress. 50 These findings indicate that augmenting endothelial-specific l-arginine transport can prevent oxidative stress in addition to augmenting NO bioavailability.…”

Section: Reduced No Bioavailability Can Lead To Oxidative Stressmentioning

confidence: 79%

“…Furthermore, a functionally relevant genetic polymorphism relating to l-arginine transport is present in human essential hypertension. 51 We have previously shown that l-arginine transport, assessed both in vivo and in vitro, is reduced not only in hypertensive subjects but also in those that are genetically predisposed to hypertension. 64 Although this study did not specifically address obesity-related hypertension, hypertensive subjects had a greater body mass index than their normotensive counterparts.…”

Section: Are No Bioavailability and L-argininementioning

confidence: 99%

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Say NO to Obesity-Related Hypertension

2016

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O besity and its complications represent one of the major emerging challenges for the developed world. 1,2 Hypertension is a common sequelae of obesity, 3,4 and the obesity pandemic is estimated to contribute to 75% of cases of hypertension in men and 65% in women.1 Frequently, subjects with obesity are resistant to standard antihypertensive medication, 4 and poor understanding of the precise mechanisms underlying the link between obesity and hypertension has presented roadblocks for the development of new and effective therapy. 4 In this context, we recently found that obesity is associated with reduced nitric oxide (NO) bioavailability caused by impaired transport of its substrate l-arginine and that augmentation of endothelial l-arginine transport prevents experimental obesity-induced hypertension.5 Findings by others also provide clear evidence that endothelial dysfunction plays an important role in the pathogenesis of hypertension 6,7 including that associated with obesity. 8In the current review, we will discuss the role of the l-arginine-NO pathway in the long-term regulation of blood pressure, its complex inter-relationship with other key neurohormonal and biochemical determinants of arterial pressure, and the way in which this system becomes deranged in obesity-related hypertension. l-Arginine-NO PathwayNO is well recognized as a pivotal endogenous modulator of vascular tone and endothelial function.9 l-Arginine is the sole substrate for NO formation and transport of extracellular l-arginine via cationic amino acid transporter-1 (CAT1) is a rate limiting factor for endothelial NO synthase (eNOS)-dependent NO formation (Figure 1). [9][10][11] This occurs despite the fact that intracellular concentration of l-arginine far exceeds the Michaelis constant K m of eNOS for l-arginine, and this phenomenon is commonly referred to as the l-arginine paradox. 9 The precise factors underlying this paradox remain to be determined, but some of the proposed mechanisms include sequestration of intracellular l-arginine into pools that are not accessible to membrane-bound eNOS, the presence of endogenous eNOS inhibitors such as asymmetrical dimethylarginine and colocalization of CAT1, and eNOS within the plasma membrane of endothelial cells, which facilitates the use of extracellular l-arginine for eNOS-dependent NO formation.9-11 Regardless of the mechanism(s) involved, the presence of the l-arginine paradox creates a crucial role for l-arginine transporters in regulating NO bioavailability and consequently endothelial function. Does Endothelial Dysfunction Precede Hypertension in the Setting of Obesity?Although there is a plethora of data to support an association between endothelial dysfunction and hypertension, [12][13][14] the precise relationship between these 2 phenomena remains complex and undefined. Weisbrod et al 15 recently demonstrated that endothelial function as measured by aortic relaxation to acetylcholine ex vivo was impaired within 2 months of placing mice on a high fat, high sucrose diet. Howeve...

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Section: Reduced No Bioavailability Can Lead To Oxidative Stressmentioning

confidence: 79%

Section: Are No Bioavailability and L-argininementioning

confidence: 99%

Say NO to Obesity-Related Hypertension

2016

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“…For example, some patients with congestive heart failure have an abnormality in L-arginine transport due to a decreased level of Cat-1 mRNA (4). Furthermore, a recently identified cytosine to uracil polymorphism in the 3Ј-untranslated region (3Ј-UTR) 2 of the human Cat-1 mRNA seems to attenuate its expression level and contributes to hypertension and endothelial dysfunction (5). Elevated Cat-1 expression has also been reported to contribute to the pathogenesis of kidney hyperfiltration in diabetic rats.…”

mentioning

confidence: 99%

A Bifunctional Intronic Element Regulates the Expression of the Arginine/Lysine Transporter Cat-1 via Mechanisms Involving the Purine-rich Element Binding Protein A (Purα)

Huang¹,

Chiribau²,

Majumder³

et al. 2009

Journal of Biological Chemistry

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“…Examples include our data for the T825 allele of the C285T polymorphism of the G-protein ␤3 subunit gene (GNB3) with hypertension and blood pressure, 90 the A1166C variant of the angiotensin II type 1 receptor gene (AGTR1), 91 and the T-344C and A6547G polymorphisms of the aldosterone synthase gene (CYP11B2), especially after analysis of haplotypes, 92 among others. [93][94][95][96][97][98] It also might have helped explain why we found no association with hypertension in the case of polymorphisms in certain additional genes for which positive association findings had been reported. 99 -105 Our glucocorticoid receptor gene (NR3C1) data were, however, weak.…”

Section: Importance Of Choosing Only Subjects With Two Hypertensive Pmentioning

confidence: 74%