Dietary Nitrate Supplementation Improves Revascularization in Chronic Ischemia

Hendgen‐Cotta, Ulrike B.; Luedike, Peter; Totzeck, Matthias; Kropp, Martina; Schicho, Andreas; Stock, Pia; Rammos, Christos; Niessen, Michael; Heiß, Christian; Lundberg, Jon O.; Weitzberg, Eddie; Kelm, Malte; Rassaf, Tienush

doi:10.1161/circulationaha.112.112912

Cited by 99 publications

(73 citation statements)

References 51 publications

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“…Further, in addition to direct vasodilatory effects, nitrite has been reported to have preconditioning-like effects in settings of ischaemia-reperfusion injury in different tissues 58 through NO-and cGMP-independent mechanisms, 59 and orally administered nitrate has been shown to improve revascularization in chronically ischaemic limbs and decrease platelet activity. 60,61 At the cellular level, nitrite has been shown to inhibit mitochondrial ROS generation and decrease leukocyte recruitment at sites of inflammation. 62 More recently, Dejam et al found that nitrite is a relatively potent and fast vasodilator at near-physiological concentrations and, interestingly, that nitrite functions as an endocrine reservoir of NO by producing remote vasodilation, with a selective preference for oxygendeprived territories.…”

Section: Nitrate Tolerancementioning

confidence: 99%

More answers to the still unresolved question of nitrate tolerance

Münzel

Daiber

Gori

2013

European Heart Journal

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Organic nitrates are traditionally felt to be a safe adjuvant in the chronic therapy of patients with coronary artery disease. Despite their long use, progress in the understanding of the pharmacology and mechanism of action of these drugs has been achieved only in the last two decades, with the identification of the role of oxidative stress in the pathophysiology of nitrate tolerance, with, the discovery of the ancillary effects of nitrates, and with the demonstration that nitrate therapy has important chronic side effects that might modify patients' prognosis. These advances are however mostly confined to the molecular level or to studies in healthy volunteers, and the true impact of organic nitrates on clinical outcome remains unknown. Complicating this issue, evidence supports the existence of important differences among the different drugs belonging to the group, and there are reasons to believe that the nitrates should not be treated as a homogeneous class. As well, the understanding of the effects of alternative nitric oxide (NO) donors is currently being developed, and future studies will need to test whether the properties of these new medications may compensate and prevent the abnormalities imposed by chronic nitrate therapy. Intermittent therapy with nitroglycerin and isosorbide mononitrate is now established in clinical practice, but they should neither be considered a definitive solution to the problem of nitrate tolerance. Both these strategies are not deprived of complications, and should currently be seen as a compromise rather than a way fully to exploit the benefits of NO donor therapy.--

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Section: Nitrate Tolerancementioning

confidence: 99%

Circulating Nitrite Contributes to Cardioprotection by Remote Ischemic Preconditioning

Rassaf

Totzeck

Hendgen‐Cotta

et al. 2014

Circulation Research

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304

267

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Rationale: Remote ischemic preconditioning (rIPC) with short episodes of ischemia/reperfusion (I/R) of an organ remote from the heart is a powerful approach to protect against myocardial I/R injury. The signal transduction pathways for the cross talk between the remote site and the heart remain unclear in detail.Objective: To elucidate the role of circulating nitrite in cardioprotection by rIPC. Methods and Results: Mice were subjected to 4 cycles of no-flow ischemia with subsequent reactive hyperemia within the femoral region and underwent in vivo myocardial I/R (30 minutes/5 minutes or 24 hours). The mouse experiments were conducted using genetic and pharmacological approaches. Shear stress-dependent stimulation of endothelial nitric oxide synthase within the femoral artery during reactive hyperemia yielded substantial release of nitric oxide, subsequently oxidized to nitrite and transferred humorally to the myocardium. Within the heart, reduction of nitrite to nitric oxide by cardiac myoglobin and subsequent S-nitrosation of mitochondrial membrane proteins reduced mitochondrial respiration, reactive oxygen species formation, and myocardial infarct size. Pharmacological and genetic inhibition of nitric oxide/nitrite generation by endothelial nitric oxide synthase at the remote site or nitrite bioactivation by myoglobin within the target organ abrogated the cardioprotection by rIPC. Transfer experiments of plasma from healthy volunteers subjected to rIPC of the arm identified plasma nitrite as a cardioprotective agent in isolated Langendorff mouse heart preparations exposed to I/R. Conclusions:

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“…23,24 Therefore, therapeutic angiogenesis remains an unmet medical need. However, a tremendous interindividual variability exists in the degree of new collateral formation in patients with coronary artery disease.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Aldehyde Dehydrogenase 2 Regulates Revascularization in Chronic Ischemia

Liu

Sun

Liao

et al. 2015

ATVB

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Objective— Revascularization is an essential process to compensate for cardiac underperfusion and, therefore, preserves cardiac function in the face of chronic ischemic injury. Recent evidence suggested a vital role of aldehyde dehydrogenase 2 (ALDH2) in cardiac protection after ischemia. This study was designed to determine whether ALDH2 regulates chronic ischemia−induced angiogenesis and to explore the underlying mechanism involved. Moreover, the clinical impact of the ALDH2 mutant allele on the development of coronary collateral circulation (CCC) was evaluated. Approach and Results— Mice limb ischemia was performed. Compared with wild-type, ALDH2 deletion significantly reduced perfusion recovery, small artery and capillary density, and increased muscle atrophy in this ischemic model. In vitro, ALDH2-knockdown reduced proliferation, migration and hypoxia triggered endothelial tube formation of endothelial cells, the effects of which were restored by ALDH2 transfection. Further examination revealed that ALDH2 regulated angiogenesis possibly through hypoxia-inducible factor-1α/vascular endothelial growth factor pathways. To further discern the role of ALDH2 deficiency in the function of bone marrow stem/progenitor cells, cross bone marrow transplantation was performed between wild-type and ALDH2-knockout mice. However, there was no significant improvement for wild-type bone marrow transplantation into knockout mice. ALDH2 genotyping was screened in 139 patients with chronic total occlusion recruited to Zhongshan Hospital (2011.10–2014.4). Patients with poor CCC (Rentrop 0–1; n=51) exhibited a higher frequency of the AA genotype than those with enriched CCC (Rentrop 2–3; n=88; 11.76% versus 1.14%; P =0 0.01). However, the AA group displayed less enriched CCC frequency in Logistic regression model when compared with the GG group (odds ratio=0.08; 95% confidence interval, 0.009–0.701; P =0 0.026). Furthermore, serum vascular endothelial growth factor level tended to be lower in patients with ALDH2 mutation. Conclusions— This study demonstrated that ALDH2 possesses an intrinsic capacity to regulate angiogenesis via hypoxia-inducible factor-1α and vascular endothelial growth factor. Patients with ALDH2-deficient genotype displayed a higher risk of developing poor CCC. Therapeutic individualization based on ALDH2 allele distribution may thus improve the therapeutic benefit, especially in the East Asian decedents.

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Dietary Nitrate Supplementation Improves Revascularization in Chronic Ischemia

Cited by 99 publications

References 51 publications

More answers to the still unresolved question of nitrate tolerance

More answers to the still unresolved question of nitrate tolerance

Circulating Nitrite Contributes to Cardioprotection by Remote Ischemic Preconditioning

Mitochondrial Aldehyde Dehydrogenase 2 Regulates Revascularization in Chronic Ischemia

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