L-arginine, tetrahydrobiopterin, nitric oxide and diabetes

Hoang, Hai H.; Padgham, Samuel; Meininger, Cynthia J.

doi:10.1097/mco.0b013e32835ad1ef

Cited by 53 publications

(34 citation statements)

References 41 publications

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“…Some of the proinflammatory interactions these receptors mediate include reactive radical formation by NOX enzymes and nitric oxide synthase (iNOS) (Barlovic et al, 2010;Herold et al, 2007;Koulis et al, 2015;Nienhuis et al, 2009;Yan et al, 2003). The catalytic activity of the latter requires the reducing cofactor tetrahydrobiopterin (Hoang et al, 2013). The oxidation of tetrahydrobiopterin by electrophiles, which are abundant in cells exposed to high glucose levels, leads to the uncoupling of the inducible NO synthase (iNOS) and results in an abnormal generation of superoxide radicals rather than NO radicals (Negre-Salvayre et al, 2010).…”

Section: Free Radicals In Diabetesmentioning

confidence: 99%

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

Maulucci

Daniel

Cohen

et al. 2016

Molecular Aspects of Medicine

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Section: Free Radicals In Diabetesmentioning

confidence: 99%

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

Maulucci

Daniel

Cohen

et al. 2016

Molecular Aspects of Medicine

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“…14 It is well accepted that hyperglycemia itself induces excessive ROS production, impairs eNOS function, and reduces NO bioavailability. 15,16 Hence, such conditions aggravate cardiovascular dysfunction and result in the failure of protection of the diabetic heart against I/R injury. 3,15,17 The polyphenolic compound luteolin, widely distributed in vegetables, fruits, and nuts, 18,19 is consumed regularly in the human diet and has been shown to reduce mortality from coronary artery diseases.…”

Section: Introductionmentioning

confidence: 99%

Cardioprotective Effects of Luteolin on Ischemia/Reperfusion Injury in Diabetic Rats Are Modulated by eNOS and the Mitochondrial Permeability Transition Pathway

Yang

Qian

Zhang

et al. 2015

Journal of Cardiovascular Pharmacology

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Myocardial ischemia/reperfusion (I/R) injury in diabetes is associated with oxidative stress, endothelial nitric oxide synthase (eNOS) dysfunction, and mitochondrial collapse, whereas luteolin is known to protect the cardiovascular system against diabetes and I/R injury. Here, we investigated whether luteolin pretreatment diminishes myocardial I/R injury in diabetic rats by affecting eNOS and the mitochondrial permeability transition pore (mPTP). After diabetic rats were produced by streptozotocin treatment (65 mg/kg) for 3 weeks, luteolin (100 mg·kg·d) or L-NAME (25 mg·kg·d) was administered intragastrically for 2 weeks. Hearts were then isolated and subjected to 30 minutes of global ischemia followed by 120 minutes of reperfusion. Pretreatment with luteolin significantly improved left ventricular function and coronary flow throughout reperfusion, increased cardiac tissue viability and manganese superoxide dismutase (MnSOD) activity, and reduced coronary lactate dehydrogenase release, and the myocardial malonaldehyde level in diabetic I/R rat hearts. All these improving effects of luteolin were significantly attenuated by L-NAME. Luteolin also significantly upregulated eNOS expression in diabetic rat hearts after I/R. Ca-induced mPTP opening and mitochondrial inner membrane potential reduction were significantly inhibited in ventricular myocytes isolated from luteolin-treated diabetic rats, and this effect was attenuated by L-NAME. These findings indicate that luteolin protects the diabetic heart against I/R injury by upregulating the myocardial eNOS pathway, and downstream effects include the enhancement of MnSOD and inhibition of mPTP.

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“…However, the available literature on the beneficial effects of L-arginine is inconclusive mainly due to inconsistent concentrations of L-arginine used and the duration of treatment. 26 A combination of sepiapterin and L-arginine diet supplementation has been shown to decrease progression of glomerular injury. 13 Improved vasorelaxation of aortae from apolipoprotein E and LDLreceptor knockout mice were achieved by treating the vessels (not through feeding) with a combination of L-arginine and BH4.…”

mentioning

confidence: 99%

Enhancing eNOS activity with simultaneous inhibition of IKKβ restores vascular function in Ins2Akita+/− type-1 diabetic mice

Krishnan

Janardhanan

Roman

et al. 2015

Laboratory Investigation

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The balance of nitric oxide (NO) versus superoxide generation has a major role in the initiation and progression of endothelial dysfunction. Under conditions of high glucose, endothelial nitric oxide synthase (eNOS) functions as a chief source of superoxide rather than NO. In order to improve NO bioavailability within the vessel wall in type-1 diabetes, we investigated treatment strategies that improve eNOS phosphorylation and NO-dependent vasorelaxation. We evaluated methods to increase the eNOS activity by (1) feeding Ins2Akita spontaneously diabetic (type-1) mice with L-arginine in the presence of sepiapterin, a precursor of tetrahydrobiopterin; (2) preventing eNOS/NO deregulation by the inclusion of inhibitor kappa B kinase beta (IKKβ) inhibitor, salsalate, in the diet regimen in combination with L-arginine and sepiapterin; and (3) independently increasing eNOS expression to improve eNOS activity and associated NO production through generating Ins2Akita diabetic mice that overexpress human eNOS predominantly in vascular endothelial cells. Our results clearly demonstrated that diet supplementation with L-arginine, sepiapterin along with salsalate improved phosphorylation of eNOS and enhanced vasorelaxation of thoracic/abdominal aorta in type-1 diabetic mice. More interestingly, despite the overexpression of eNOS, the in-house generated transgenic eNOS-GFP (TgeNOS-GFP)-Ins2 Akita cross mice showed an unanticipated effect of reduced eNOS phosphorylation and enhanced superoxide production. Our results demonstrate that enhancement of endogenous eNOS activity by nutritional modulation is more beneficial than increasing the endogenous expression of eNOS by gene therapy modalities. Endothelial nitric oxide synthase (eNOS) that utilizes L-arginine as a substrate to generate nitric oxide (NO) is a key regulator of vascular function. Even though endothelial cells, a predominant source of eNOS exhibit constitutive enzyme activity, several other regulators are necessary to induce eNOS activity based on local demand for NO. Reduced bioavailability of NO that causes endothelial dysfunction is a hallmark of diabetes. Several mechanisms have been implicated causing 'endothelial dysfunction' in diabetes. The reduced availability of the substrate L-arginine and the cofactor tetrahydrobiopterin (BH4) has been implicated due to increased arginase activity and enhanced superoxide generation. 1 Uncoupling of eNOS has been shown to be central to robust superoxide generation and the associated vascular dysfunction. 2 Increased levels of asymmetric NG, NG-dimethyl arginine (ADMA-a substrate analog of L-arginine) in circulation have also been shown in diabetic patients limiting the availability of L-arginine to eNOS. 3 In vitro studies from our laboratory and reports from other investigators have shown that the regulation of eNOS activity is mediated by heat shock protein-90 (Hsp-90). 4,5 The interaction of eNOS with Hsp-90 favors the phosphorylation of eNOS at Ser1177 by Akt kinase. This phosphorylation process is a key event which a...

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L-arginine, tetrahydrobiopterin, nitric oxide and diabetes

Abstract: Restoring proper eNOS activity is key to ameliorating or preventing cardiovascular complications of diabetes. Continued investigation is needed to uncover new means for maintaining endothelial nitric oxide bioavailability.

Cited by 53 publications

References 41 publications

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

Cardioprotective Effects of Luteolin on Ischemia/Reperfusion Injury in Diabetic Rats Are Modulated by eNOS and the Mitochondrial Permeability Transition Pathway

Enhancing eNOS activity with simultaneous inhibition of IKKβ restores vascular function in Ins2Akita+/− type-1 diabetic mice

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