Jon O Lundberg

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (233)1609.59 Total impact

  • Jon O Lundberg · Mark T Gladwin · Eddie Weitzberg
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    ABSTRACT: Nitric oxide (NO) is a key signalling molecule in the cardiovascular, immune and central nervous systems, and crucial steps in the regulation of NO bioavailability in health and disease are well characterized. Although early approaches to therapeutically modulate NO bioavailability failed in clinical trials, an enhanced understanding of fundamental subcellular signalling has enabled a range of novel therapeutic approaches to be identified. These include the identification of: new pathways for enhancing NO synthase activity; ways to amplify the nitrate-nitrite-NO pathway; novel classes of NO-donating drugs; drugs that limit NO metabolism through effects on reactive oxygen species; and ways to modulate downstream phosphodiesterases and soluble guanylyl cyclases. In this Review, we discuss these latest developments, with a focus on cardiovascular disease.
    Nature Reviews Drug Discovery 08/2015; 14(9). DOI:10.1038/nrd4623 · 41.91 Impact Factor
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    ABSTRACT: Accumulating studies suggest that nitric oxide (NO) deficiency and oxidative stress are central pathological mechanisms in type 2 diabetes (T2D). Recent findings demonstrate therapeutic effects by boosting the nitrate-nitrite-NO pathway, which is an alternative pathway for NO formation. This study aimed at investigating the acute effects of inorganic nitrate on glucose and insulin signaling in adenosine A2B receptor knockout mice (A(-/-) 2B), a genetic mouse model of impaired metabolic regulation. Acute effects of nitrate treatment were investigated in aged wild-type (WT) and A(-/-) 2B mice. One hour after injection with nitrate (0.1 mmol/kg, i.p.) or placebo, metabolic regulation was evaluated by intraperitoneal glucose and insulin tolerance tests. NADPH oxidase-mediated superoxide production and AMPK phosphorylation were measured in livers obtained from non-treated or glucose-treated mice, with or without prior nitrate injection. Plasma was used to determine insulin resistance (HOMA-IR) and NO signaling. A(-/-) 2B displayed increased body weight, reduced glucose clearance, and attenuated overall insulin responses compared with age-matched WT mice. Nitrate treatment increased circulating levels of nitrate, nitrite and cGMP in the A(-/-) 2B, and improved glucose clearance. In WT mice, however, nitrate treatment did not influence glucose clearance. HOMA-IR increased following glucose injection in the A(-/-) 2B, but remained at basal levels in mice pretreated with nitrate. NADPH oxidase activity in livers from A(-/-) 2B, but not WT mice, was reduced by nitrate treatment. Livers from A(-/-) 2B displayed reduced AMPK phosphorylation compared with WT mice, and this was increased by nitrate treatment. Finally, injection with the anti-diabetic agent metformin induced similar therapeutic effects in the A(-/-) 2B as observed with nitrate. The A(-/-) 2B mouse is a genetic mouse model of metabolic syndrome. Acute treatment with nitrate improved the metabolic profile in it, at least partly via reduction in oxidative stress and improved AMPK signaling in the liver.
    Frontiers in Physiology 07/2015; DOI:10.3389/fphys.2015.00222 · 3.53 Impact Factor
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    ABSTRACT: Inorganic nitrate (NO3(-)) is a precursor of nitric oxide (NO) in the body and a large number of short-term studies with dietary nitrate supplementation in animals and humans show beneficial effects on cardiovascular health, exercise efficiency, host defense and ischemia reperfusion injury. In contrast, there is a long withstanding concern regarding the putative adverse effects of chronic nitrate exposure related to cancer and adverse hormonal effects. To address these concerns we performed in mice, a physiological and biochemical multi-analysis on the effects of long-term dietary nitrate supplementation. 7 week-old C57BL/6 mice were put on a low-nitrate chow and at 20 weeks-old were treated with NaNO3 (1mmol/L) or NaCl (1mmol/L, control) in the drinking water. The groups were monitored for weight gain, food and water consumption, blood pressure, glucose metabolism, body composition and oxygen consumption until one group was reduced to eight animals due to death or illness. At that point remaining animals were sacrificed and blood and tissues were analyzed with respect to metabolism, cardiovascular function, inflammation, and oxidative stress. Animals were supplemented for 17 months before final sacrifice. Body composition, oxygen consumption, blood pressure, glucose tolerance were measured during the experiment, and vascular reactivity and muscle mitochondrial efficiency measured at the end of the experiment with no differences identified between groups. Nitrate supplementation was associated with improved insulin response, decreased plasma IL-10 and a trend towards improved survival. Long term dietary nitrate in mice, at levels similar to the upper intake range in the western society, is not detrimental. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
    05/2015; 22. DOI:10.1016/j.redox.2015.05.004
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    ABSTRACT: The current study describes novel multifunctional polymer-shelled microbubbles (MBs) loaded with nitric oxide (NO) for integrated therapeutic and diagnostic applications (ie, theranostics) of myocardial ischemia. We used gas-filled MBs with an average diameter of 4 μm stabilized by a biocompatible shell of polyvinyl alcohol. In vitro acoustic tests showed sufficient enhancement of the backscattered power (20 dB) acquired from the MBs' suspension. The values of attenuation coefficient (0.8 dB/cm MHz) and phase velocities (1,517 m/s) were comparable with those reported for the soft tissue. Moreover, polymer MBs demonstrate increased stability compared with clinically approved contrast agents with a fracture threshold of about 900 kPa. In vitro chemiluminescence measurements demonstrated that dry powder of NO-loaded MBs releases its gas content in about 2 hours following an exponential decay profile with an exponential time constant equal to 36 minutes. The application of high-power ultrasound pulse (mechanical index =1.2) on the MBs resuspended in saline decreases the exponential time constant from 55 to 4 minutes in air-saturated solution and from 17 to 10 minutes in degassed solution. Thus, ultrasound-triggered release of NO is achieved. Cytotoxicity tests indicate that phagocytosis of the MBs by macrophages starts within 6-8 hours. This is a suitable time for initial diagnostics, treatment, and monitoring of the therapeutic effect using a single injection of the proposed multifunctional MBs.
    Drug Design, Development and Therapy 04/2015; 9:2409-19. DOI:10.2147/DDDT.S77790 · 3.03 Impact Factor
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    ABSTRACT: The kidney is vulnerable to hypoxia, and substantial efforts have been made to ameliorate renal ischemic injury secondary to pathological conditions. Stimulation of the nitrate-nitrite-nitric oxide pathway is associated with renal and cardiovascular protection in disease models, but less is known about the vascular effects during renal ischemia. This study aimed at investigating the vascular effects of nitrite in the kidney during normoxia and ischemic condition. Using a multi wire myograph system, nitrite-mediated relaxation (10(-9)-10(-4)mol/L) was assessed in preconstricted isolated renal interlobar arteries (ILA) from C57BL6 mice during normal conditions (pO213kPa; pH 7.4) and with low oxygen tension and low pH to mimic ischemia (pO2 3kPa; pH 6.6). Xanthine oxidoreductase expression was analyzed by quantitative PCR, and production of reactive nitrogen species was measured by DAF-FM DA fluorescence. During normoxia significant vasodilatation (15±3%) was observed only at the highest concentration of nitrite, which was dependent on NO-sGC-cGMP-signaling. The vasodilatory responses to nitrite were greatly sensitized and enhanced during hypoxia with low pH, demonstrating significant dilatation (11±1%) already in the physiological range (10(-8)mol/L), with a maximum response of 27±2% at 10(-4)mol/L. In contrast to normoxia, and to that observed with a classical NO donor (DEA NONOate) this sensitization was independent of sGC-cGMP-signaling. Moreover, inhibition of different enzymatic systems reported to reduce nitrite in other vascular beds, i.e. aldehyde oxidase (raloxifene), aldehyde dehydrogenase (cyanamide) and NO synthase (L-NAME) had no effect on the nitrite response. However, inhibition of xanthine oxidoreductase (febuxostat or allopurinol) abolished the sensitized response to nitrite during hypoxia and acidosis. In conclusion, in contrast to normoxia, nitrite exerted potent vasorelaxation during ischemic condition already at physiological concentrations. This effect was dependent on functional XOR while independent of classical downstream signaling by sGC-cGMP. Copyright © 2015. Published by Elsevier Inc.
    Free Radical Biology and Medicine 04/2015; 84. DOI:10.1016/j.freeradbiomed.2015.03.025 · 5.74 Impact Factor
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    ABSTRACT: The underlying pathogenic mechanisms of neurological complications in infants undergoing peritoneal dialysis (PD) are poorly understood. We report on four male infants treated with PD who developed symptomatic cerebral ischaemia. Blood pressure (BP) levels were low both before the event and at presentation. In two patients, we observed that the removal of nitrate and nitrite by PD could have impaired the nitrate/nitrite–-nitrite oxide (NO) pathway, a system that generates NO independently of NO synthase. Our observation suggests that low BP and reduced NO bioavailability puts infants treated with PD at risk for impaired cerebral blood flow and consequently for brain ischaemia.
    CKJ: Clinical Kidney Journal 02/2015; online(2). DOI:10.1093/ckj/sfv009
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    ABSTRACT: Dietary intervention studies have shown that flavanols and inorganic nitrate can improve vascular function, suggesting that these two bioactives may be responsible for beneficial health effects of diets rich in fruits and vegetables. To study interactions between cocoa flavanols (CF) and nitrate focusing on absorption, bioavailability, excretion, and efficacy to increase endothelial function. In a double-blind randomized, dose-response cross-over study, flow-mediated dilation (FMD) was measured in 15 healthy subjects before and at 1, 2, 3, and 4h following consumption of CF (1.4-10.9mg/kg body weight [bw]) or nitrate (0.1-10mg/kg bw). In order to study flavanol-nitrate interactions, an additional intervention trial was performed with nitrate and CF taken in sequence at low and high amounts. FMD was measured before (0h) and at 1h after ingestion of nitrate (3 or 8.5mg/kg bw) or water. Then subjects received a CF drink (2.7 or 10.9mg/kg bw) or a micro- and macronutrient matched CF-free drink. FMD was measured at 1, 2, and 4h thereafter. Blood and urine samples were collected and assessed for CF and NO-metabolites with HPLC and gas phase reductive chemiluminescence. Finally, intragastric formation of nitric oxide (NO) after CF and nitrate consumption was investigated. Both CF and nitrate induced a similar intake-dependent increase in FMD. Maximal values were achieved at 1h post ingestion and gradually decreased to reach baseline values at 4h. These effects were additive at low intake levels whereas CF did not further increase FMD after high nitrate intake. Nitrate did not affect flavanol absorption, bioavailability, or excretion but CF enhanced nitrate-related gastric NO formation and attenuated the increase in plasma nitrite after nitrate intake. Both flavanols and inorganic nitrate can improve endothelial function in healthy subjects at intake amounts that are achievable with a normal diet. Even low dietary intake of these bioactives may exert relevant effects on endothelial function when ingested together. Copyright © 2014 Elsevier Inc. All rights reserved.
    Free Radical Biology and Medicine 12/2014; 80. DOI:10.1016/j.freeradbiomed.2014.12.009 · 5.74 Impact Factor
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    ABSTRACT: Sphingolipids are important components of neurons and the myelin sheath whose levels are altered in multiple sclerosis (MS). We aimed to determine if cerebrospinal fluid (CSF) sphingolipids can be used as markers of MS disease progression. Using liquid chromatography tandem mass spectrometry, we analysed sphingolipids in CSF from 134 individuals. The MS group included 65 patients divided into 41 relapsing-remitting MS (RRMS) and 24 progressive MS (ProgMS). In addition, a group of 13 early MS/clinically isolated syndrome (EarlyMS) and two control groups consisting of 38 individuals with other neurological diseases (OND) and 18 OND with signs of inflammation (iOND) were analysed. A follow-up study included 17 additional RRMS patients sampled at two time points 4.7±1.7 years apart. Levels of sphingomyelin (SM)- and hexosylceramide (HexCer)-derived sphingolipids increased in the CSF of patients with MS independently of the fatty acid chain length in RRMS (p<0.05). Levels of palmitic acid (16:0)-containing HexCer (HexCer16:0) increased significantly in ProgMS compared with the OND (p<0.001), iOND (p<0.05) and EarlyMS (p<0.01) groups and correlated with Expanded Disability Status Scale in RRMS in both studies (p=0.048; p=0.027). HexCer16:0 is a promising candidate marker of disease progression in MS, especially in RRMS. © The Author(s), 2014.
    Multiple Sclerosis 12/2014; 21(10). DOI:10.1177/1352458514561908 · 4.82 Impact Factor
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    ABSTRACT: The significance of nasal resonance and anti-resonance to voice production is a classical issue in vocal pedagogy and voice research. The complex structure of the nasal tract produces a complex frequency response. This complexity must be heavily influenced by the morphology of the paranasal cavities, but their contributions are far from being entirely understood. Detailed analyses of these cavities are difficult because of their limited accessibility. Here we test different methods aiming at documenting the acoustical properties of the paranasal tract. The first set of experiments was performed under in vivo conditions, where the middle meatus was occluded by means of targeted application of a maltodextrin mass under endoscopic control. The efficiency of this occlusion method was verified by measuring the nasal nitric oxide (NO) output during humming. In another experiment the frequency responses to sine sweep excitation of an epoxy mould of a nasal cavity were measured, with and without elimination of paranasal sinuses. The third experiment was conducted in a cadaveric situs, with and without maltodextrin occlusion of the middle meatus and the sphenoidal ostia. The results show that some nasal tract resonances were unaffected by the manipulation of the paranasal cavities. Providing access to a maxillary sinus resulted in marked dips in the response curve while access to the sphenoidal ostium caused only minor effects.
    Logopedics Phoniatrics Vocology 10/2014; DOI:10.3109/14015439.2014.967364 · 0.93 Impact Factor
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    ABSTRACT: Renal oxidative stress and nitric oxide (NO) deficiency are key events in hypertension. Stimulation of a nitrate-nitrite-NO pathway with dietary nitrate reduces blood pressure, but the mechanisms or target organ are not clear. We investigated the hypothesis that inorganic nitrate and nitrite attenuate reactivity of renal microcirculation and blood pressure responses to angiotensin II (ANG II) by modulating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NO bioavailability. Nitrite in the physiological range (10(-7)-10(-5) mol/L) dilated isolated perfused renal afferent arterioles, which were associated with increased NO. Contractions to ANG II (34%) and simultaneous NO synthase inhibition (56%) were attenuated by nitrite (18% and 26%). In a model of oxidative stress (superoxide dismutase-1 knockouts), abnormal ANG II-mediated arteriolar contractions (90%) were normalized by nitrite (44%). Mechanistically, effects of nitrite were abolished by NO scavenger and xanthine oxidase inhibitor, but only partially attenuated by inhibiting soluble guanylyl cyclase. Inhibition of NADPH oxidase with apocynin attenuated ANG II-induced contractility (35%) similar to that of nitrite. In the presence of nitrite, no further effect of apocynin was observed, suggesting NADPH oxidase as a possible target. In preglomerular vascular smooth muscle cells and kidney cortex, nitrite reduced both basal and ANG II-induced NADPH oxidase activity. These effects of nitrite were also abolished by xanthine oxidase inhibition. Moreover, supplementation with dietary nitrate (10(-2) mol/L) reduced renal NADPH oxidase activity and attenuated ANG II-mediated arteriolar contractions and hypertension (99±2-146±2 mm Hg) compared with placebo (100±3-168±3 mm Hg). In conclusion, these novel findings position NADPH oxidase in the renal microvasculature as a prime target for blood pressure-lowering effects of inorganic nitrate and nitrite.
    Hypertension 10/2014; 65(1). DOI:10.1161/HYPERTENSIONAHA.114.04222 · 6.48 Impact Factor
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    ABSTRACT: The maximum power principle dictates that open biological systems tend to self-organize to a level of efficiency that allows maximal power production. Applying this principle to cellular energetics and whole-body physiology would suggest that for every metabolic challenge, an optimal efficiency exists that maximizes power production. On exposure to hypoxia, it would be favorable if metabolic efficiency would rapidly adjust so as to better preserve work performance. We tested this idea in humans by measuring metabolic efficiency and exercise tolerance under normoxic (Fi(O)2=20.9%) and hypoxic (Fi(O)2=16%) conditions, where Fi(O)2 is fraction of inhaled oxygen. The results were compared with respirometric analyses of skeletal muscle mitochondria from the same individuals. We found that among healthy trained subjects (n=14) with a wide range of metabolic efficiency (ME), those with a high ME during normoxic exercise were able to better maintain exercise capacity (Wmax) in hypoxia. On hypoxic exposure, these subjects acutely decreased their efficiency from 19.2 to 17.4%, thereby likely shifting it closer to a degree of efficiency where maximal power production is achieved. In addition, mitochondria from these subjects had a lower intrinsic respiration compared to subjects that showed a large drop in Wmax in hypoxia An acute shift in efficiency was also demonstrated in isolated mitochondria exposed to physiological levels of hypoxia as P/O ratio increased from 0.9 to 1.3 with hypoxic exposure. These findings suggest the existence of a physiological adaptive response by which metabolic efficiency is dynamically optimized to maximize power production.-Schiffer, T. A., Ekblom, B., Lundberg, J. O., Weitzberg, E., Larsen, F. J. Dynamic regulation of metabolic efficiency explains tolerance to acute hypoxia in humans.
    The FASEB Journal 06/2014; 28(10). DOI:10.1096/fj.14-251710 · 5.04 Impact Factor
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    ABSTRACT: Thioredoxin-related protein of 14 kDa (TRP14, also called TXNDC17 for thioredoxin domain containing 17, or TXNL5 for thioredoxin-like 5) is an evolutionarily well-conserved member of the thioredoxin (Trx)-fold protein family that lacks activity with classical Trx1 substrates. However, we discovered here that human TRP14 has a high enzymatic activity in reduction of l-cystine, where the catalytic efficiency (2,217 min(-1)⋅µM(-1)) coupled to Trx reductase 1 (TrxR1) using NADPH was fivefold higher compared with Trx1 (418 min(-1)⋅µM(-1)). Moreover, the l-cystine reduction with TRP14 was in contrast to that of Trx1 fully maintained in the presence of a protein disulfide substrate of Trx1 such as insulin, suggesting that TRP14 is a more dedicated l-cystine reductase compared with Trx1. We also found that TRP14 is an efficient S-denitrosylase with similar efficiency as Trx1 in catalyzing TrxR1-dependent denitrosylation of S-nitrosylated glutathione or of HEK293 cell-derived S-nitrosoproteins. Consequently, nitrosylated and thereby inactivated caspase 3 or cathepsin B could be reactivated through either Trx1- or TRP14-catalyzed denitrosylation reactions. TRP14 was also, in contrast to Trx1, completely resistant to inactivation by high concentrations of hydrogen peroxide. The oxidoreductase activities of TRP14 thereby complement those of Trx1 and must therefore be considered for the full understanding of enzymatic control of cellular thiols and nitrosothiols.
    Proceedings of the National Academy of Sciences 04/2014; 111(19). DOI:10.1073/pnas.1317320111 · 9.67 Impact Factor
  • V. Kapil · E. Weitzberg · J.O. Lundberg · A. Ahluwalia
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    ABSTRACT: The discovery of nitric oxide and its role in almost every facet of human biology opened a new avenue for treatment through manipulation of its canonical signaling and by attempts to augment endogenous nitric oxide generation through provision of substrate and co-factors to the endothelial nitric oxide synthase complex. This has been particularly so in the cardiovascular system and it is well recognized that there is reduced biovailable nitric oxide in patients with both cardiovascular risk factors and manifest vascular disease. However, these attempts have failed to deliver the expected benefits of such an approach. Recently, an alternative pathway for nitric oxide synthesis has been elucidated that can produce authentic nitric oxide from the 1 electron reduction of inorganic nitrite. Furthermore, it has long been known that symbiotic, facultative, oral microflora can facilitate the reduction of inorganic nitrate, that is ingested in the average diet in millimolar amounts, to inorganic nitrite itself. Thus, there exists an alternative reductive pathway from nitrate, via nitrite as an intermediate, to nitric oxide that provides a novel pathway that may be amenable to therapeutic manipulation. As such, various research groups have explored the utility of manipulation of this nitrate-nitrite-nitric oxide pathway in situations in which nitric oxide is known to have a prominent role. Animal and early-phase human studies of both inorganic nitrite and nitrate supplementation have shown beneficial effects in blood pressure control, platelet function, vascular health and exercise capacity. This review considers in detail the pathways of inorganic nitrate bioactivation and the evidence of clinical utility to date on the cardiovascular system.
    Nitric Oxide 04/2014; 38(1). DOI:10.1016/j.niox.2014.03.162 · 3.52 Impact Factor

Publication Stats

10k Citations
1,609.59 Total Impact Points


  • 1994–2015
    • Karolinska Institutet
      • Department of Physiology and Pharmacology
      Solna, Stockholm, Sweden
  • 2014
    • Uppsala University
      • Department of Medical Cell Biology
      Uppsala, Uppsala, Sweden
  • 2012
    • Heinrich-Heine-Universität Düsseldorf
      • Faculty of Medicine
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1995–2012
    • Karolinska University Hospital
      • • Department of Cardiology
      • • Department of Urology
      • • Department of Thoracic Surgery
      Tukholma, Stockholm, Sweden
  • 2011
    • University of Coimbra
      • Centro de Neurociências e Biologia Celular (CNC)
      Coimbra, Distrito de Coimbra, Portugal
  • 2010
    • University of Texas Health Science Center at Houston
      Houston, Texas, United States
  • 2006
    • KTH Royal Institute of Technology
      • Department of Speech, Music and Hearing (TMH)
      Tukholma, Stockholm, Sweden
  • 2004
    • Nicox Research Institute
      Nice, Provence-Alpes-Côte d'Azur, France
    • Sahlgrenska University Hospital
      Goeteborg, Västra Götaland, Sweden
  • 2003
    • University of Naples Federico II
      Napoli, Campania, Italy