Systemic and Vascular Oxidation Limits the Efficacy of Oral Tetrahydrobiopterin Treatment in Patients With Coronary Artery Disease

Cunnington, Colin; Assche, Tim Van; Shirodaria, C; Kylintireas, I; Lindsay, Alistair C; Lee, J M; Antoniades, Charalambos; Margaritis, Marios; Lee, R; Cerrato, Ruha; Crabtree, Mark J.; Francis, Jane M; Sayeed, Rana; Ratnatunga, C; Pillai, Ravi; Choudhury, Robin P.; Neubauer, Stefan; Channon, Keith M.

doi:10.1161/circulationaha.111.038919

Cited by 144 publications

(124 citation statements)

References 34 publications

(34 reference statements)

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“…However, BH 4 supplementation alone does not result in complete recovery of NOS-dependent CF, although tandem replenishment including NADPH does (Reyes et al, 2015). A recent clinical study testing the effect of oral BH 4 on endothelial function in patients with coronary artery disease found that systemic and vascular oxidation of BH 4 limited its protective effects (Cunnington et al, 2012). Considering this finding, it is possible that NADPH-dependent reactions that either salvage BH 4 from its reversible oxidation products through dihydrofolate reductase (Bailey and Ayling, 2009) or complete its de novo synthesis through sepiapterin reductase (Gao et al, 2009) are limited in I/R injury, perhaps by diminished cellular NADPH levels.…”

Section: Discussionmentioning

confidence: 99%

Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H)

Boslett

Hemann

Zhao

et al. 2017

J Pharmacol Exp Ther

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We recently showed that ischemia/reperfusion (I/R) of the heart causes CD38 activation with resultant depletion of the cardiac NADP(H) pool, which is most marked in the endothelium. This NADP(H) depletion was shown to limit the production of nitric oxide by endothelial nitric oxide synthase (eNOS), which requires NADPH for nitric oxide production, resulting in greatly altered endothelial function. Therefore, intervention with CD38 inhibitors could reverse postischemic eNOS-mediated endothelial dysfunction. Here, we evaluated the potency of the CD38 inhibitor luteolinidin, an anthocyanidin, at blocking CD38 activity and preserving endothelial and myocardial function in the postischemic heart. Initially, we characterized luteolinidin as a CD38 inhibitor in vitro to determine its potency and mechanism of inhibition. We then tested luteolinidin in the ex vivo isolated heart model, where we determined luteolinidin uptake with aqueous and liposomal delivery methods. Optimal delivery methods were then further tested to determine the effect of luteolinidin on postischemic NAD(P)(H) and tetrahydrobiopterin levels. Finally, through nitric oxide synthase-dependent coronary flow and left ventricular functional measurements, we evaluated the efficacy of luteolinidin to protect vascular and contractile function, respectively, after I/R. With enhanced postischemic preservation of NADPH and tetrahydrobiopterin, there was a dose-dependent effect of luteolinidin on increasing recovery of endothelium-dependent vasodilatory function, as well as enhancing the recovery of left ventricular contractile function with increased myocardial salvage. Thus, luteolinidin is a potent CD38 inhibitor that protects the heart against I/R injury with preservation of eNOS function and prevention of endothelial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H)

Boslett

Hemann

Zhao

et al. 2017

J Pharmacol Exp Ther

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“…However, several clinical investigations, particularly long-term studies, have failed to translate these observations into clinical benefit (e.g., refs. [7][8][9]. The reasons for these discordant findings are variously attributed to an uncoupling of NOS for L-arginine (10), tolerance and induction per se of vascular dysfunction with the organic nitrates (11), and oxidation of tetrahydrobiopterin (9).…”

mentioning

confidence: 99%

“…[7][8][9]. The reasons for these discordant findings are variously attributed to an uncoupling of NOS for L-arginine (10), tolerance and induction per se of vascular dysfunction with the organic nitrates (11), and oxidation of tetrahydrobiopterin (9). These issues suggest that the failure of translation may lie in the failure of effective delivery of NO rather than a lack of efficacy of NO.…”

mentioning

confidence: 99%

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

Khambata

Ghosh

Rathod

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Reduced bioavailable nitric oxide (NO) plays a key role in the enhanced leukocyte recruitment reflective of systemic inflammation thought to precede and underlie atherosclerotic plaque formation and instability. Recent evidence demonstrates that inorganic nitrate (NO 3 − ) through sequential chemical reduction in vivo provides a source of NO that exerts beneficial effects upon the cardiovascular system, including reductions in inflammatory responses. We tested whether the antiinflammatory effects of inorganic nitrate might prove useful in ameliorating atherosclerotic disease in Apolipoprotein (Apo)E knockout (KO) mice. We show that dietary nitrate treatment, although having no effect upon total plaque area, caused a reduction in macrophage accumulation and an elevation in smooth muscle accumulation within atherosclerotic plaques of ApoE KO mice, suggesting plaque stabilization. We also show that in nitratefed mice there is reduced systemic leukocyte rolling and adherence, circulating neutrophil numbers, neutrophil CD11b expression, and myeloperoxidase activity compared with wild-type littermates. Moreover, we show in both the ApoE KO mice and using an acute model of inflammation that this effect upon neutrophils results in consequent reductions in inflammatory monocyte expression that is associated with elevations of the antiinflammatory cytokine interleukin (IL)-10. In summary, we demonstrate that inorganic nitrate suppresses acute and chronic inflammation by targeting neutrophil recruitment and that this effect, at least in part, results in consequent reductions in the inflammatory status of atheromatous plaque, and suggest that this effect may have clinical utility in the prophylaxis of inflammatory atherosclerotic disease.

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“…However, a recent clinical trial demonstrated that in patients with CAD, oral tetrahydrobiopterin treatment failed to improve endothelial function or cardiovascular outcomes, possibly due to autooxidation of the compound (47).…”

mentioning

confidence: 99%

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

Montezano

Touyz²

2014

Antioxidants & Redox Signaling

235

177

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Significance: Reactive oxygen species (ROS) are signaling molecules that are important in physiological processes, including host defense, aging, and cellular homeostasis. Increased ROS bioavailability and altered redox signaling (oxidative stress) have been implicated in the onset and/or progression of chronic diseases, including hypertension. Recent Advances: Although oxidative stress may not be the only cause of hypertension, it amplifies blood pressure elevation in the presence of other pro-hypertensive factors, such as salt loading, activation of the renin-angiotensin-aldosterone system, and sympathetic hyperactivity, at least in experimental models. A major source for ROS in the cardiovascular-renal system is a family of nicotinamide adenine dinucleotide phosphate oxidases (Noxs), including the prototypic Nox2-based Nox, and Nox family members: Nox1, Nox4, and Nox5. Critical Issues: Although extensive experimental data support a role for increased ROS levels and altered redox signaling in the pathogenesis of hypertension, the role in clinical hypertension is unclear, as a direct causative role of ROS in blood pressure elevation has yet to be demonstrated in humans. Nevertheless, what is becoming increasingly evident is that abnormal ROS regulation and aberrant signaling through redoxsensitive pathways are important in the pathophysiological processes which is associated with vascular injury and target-organ damage in hypertension. Future Directions: There is a paucity of clinical information related to the mechanisms of oxidative stress and blood pressure elevation, and a few assays accurately measure ROS directly in patients. Such further ROS research is needed in humans and in the development of adequately validated analytical methods to accurately assess oxidative stress in the clinic. Antioxid. Redox Signal. 20,[164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182]

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Systemic and Vascular Oxidation Limits the Efficacy of Oral Tetrahydrobiopterin Treatment in Patients With Coronary Artery Disease

Cited by 144 publications

References 34 publications

Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H)

Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H)

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

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