Jon O Lundberg

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (204)1162.54 Total impact

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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.
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 06/2014;
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    ABSTRACT: Nitrate, which is an inorganic anion abundant in vegetables, increases the efficiency of isolated human mitochondria. Such an effect might be reflected in changes in the resting metabolic rate (RMR) and formation of reactive oxygen species. The bioactivation of nitrate involves its active accumulation in saliva followed by a sequential reduction to nitrite, nitric oxide, and other reactive nitrogen species. We studied effects of inorganic nitrate, in amounts that represented a diet rich in vegetables, on the RMR in healthy volunteers. In a randomized, double-blind, crossover study, we measured the RMR by using indirect calorimetry in 13 healthy volunteers after a 3-d dietary intervention with sodium nitrate (NaNO3) or a placebo (NaCl). The nitrate dose (0.1 mmol ⋅ kg(-1) ⋅ d(-1)) corresponded to the amount in 200-300 g spinach, beetroot, lettuce, or other vegetable that was rich in nitrate. Effects of direct nitrite exposure on cell respiration were studied in cultured human primary myotubes. The RMR was 4.2% lower after nitrate compared with placebo administration, and the change correlated strongly to the degree of nitrate accumulation in saliva (r(2) = 0.71). The thyroid hormone status, insulin sensitivity, glucose uptake, plasma concentration of isoprostanes, and total antioxidant capacity were unaffected by nitrate. The administration of nitrite to human primary myotubes acutely inhibited respiration. Dietary inorganic nitrate reduces the RMR. This effect may have implications for the regulation of metabolic function in health and disease.
    American Journal of Clinical Nutrition 02/2014; · 6.50 Impact Factor
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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 01/2014; · 3.27 Impact Factor
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    ABSTRACT: Aims: Inorganic nitrate and nitrite from endogenous and dietary sources have emerged as alternative substrates for nitric oxide (NO) formation in addition to the classic L-arginine NO synthase (NOS)-dependent pathway. Here we investigated a potential crosstalk between these two pathways in regulation of vascular function. Results: Long-term dietary supplementation with sodium nitrate (0.1 and 1 mmol kg-1 day-1) in rats caused a reversible dose-dependent reduction in phosphorylated eNOS (Ser1177) in aorta and a concomitant increase in phosphorylation at Thr495. Moreover, eNOS-dependent vascular responses were attenuated in vessels harvested from nitrate-treated mice or when nitrite was acutely added to control vessels. The citrulline-to-arginine ratio in plasma, as a measure of eNOS activity, was reduced in nitrate-treated rodents. Telemetry measurements revealed that a low dietary nitrate dose reduced blood pressure, whereas the higher dose was associated with a paradoxical elevation. Finally, plasma cGMP increased in mice treated with a low dietary nitrate dose and decreased with a higher dose. Innovation & Conclusions: These results demonstrate the existence of a crosstalk between the nitrate-nitrite-NO pathway and the NOS-dependent pathway in control of vascular NO homeostasis.
    Antioxidants & Redox Signaling 11/2013; · 8.20 Impact Factor
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    ABSTRACT: Antibacterial nitrogen oxides including nitric oxide are formed from nitrite under acidic conditions. In a continuous-flow model of the urinary bladder we used the retention cuff of an all-silicone Foley catheter as a depot for export of nitrogen oxides. The cuff was filled with sodium nitrite (50mM) and an acidic buffer solution (pH 3.6) and the growth of nine common uropathogens in the surrounding artificial urine was measured along with biofilm formation on the catheter surface. In experiments with control catheters (NaCl) bacteria grew readily and biofilm developed within hours in five out of nine strains. In contrast, with test catheters bacterial counts were markedly reduced and biofilm formation by P. aeruginosa, K. pneumoniae and E. cloace was prevented while E. coli and S. aureus was unaffected. We conclude that antibacterial nitrogen oxides generated in the retention cuff of a urinary catheter diffuse into urine and prevent the growth of urinary pathogens and biofilm formation. Although promising, future studies will reveal if this novel approach can be clinically useful for the prevention of catheter-associated urinary tract infections.
    Free Radical Biology & Medicine 09/2013; · 5.27 Impact Factor
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    ABSTRACT: The theory that red blood cells (RBCs) generate and release nitric oxide (NO)-like bioactivity has gained considerable interest. However, it remains unclear whether it can be produced by endothelial NO synthase (eNOS), which is present in RBCs, and whether NO can escape scavenging by hemoglobin. The aim of this study was to test the hypothesis that arginase reciprocally controls NO formation in RBCs by competition with eNOS for their common substrate arginine and that RBC-derived NO is functionally active following arginase blockade. We show that rodent and human RBCs contain functional arginase 1 and that pharmacological inhibition of arginase increases export of eNOS-derived nitrogen oxides from RBCs under basal conditions. The functional importance was tested in an ex vivo model of myocardial ischemia-reperfusion injury. Inhibitors of arginase significantly improved postischemic functional recovery in rat hearts if administered in whole blood or with RBCs in plasma. By contrast, arginase inhibition did not improve postischemic recovery when administered with buffer solution or plasma alone. The protective effect of arginase inhibition was lost in the presence of a NOS inhibitor. Moreover, hearts from eNOS(-/-) mice were protected when the arginase inhibitor was given with blood from wild-type donors. In contrast, when hearts from wild-type mice were given blood from eNOS(-/-) mice, the arginase inhibitor failed to protect against ischemia-reperfusion. These results strongly support the notion that RBCs contain functional eNOS and release NO-like bioactivity. This process is under tight control by arginase 1 and is of functional importance during ischemia-reperfusion.
    Proceedings of the National Academy of Sciences 08/2013; · 9.81 Impact Factor
  • Eddie Weitzberg, Jon O Lundberg
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    ABSTRACT: The circulation of nitrogen in nature is a prerequisite for life on earth. In the nitrogen cycle atmospheric nitrogen is fixated by bacteria into forms that can be utilized by plants and mammals. Nitrate and nitrite are obligate intermediates in this cycle, and for more than half a century these anions have interested nutritional scientists, mostly in relation to cancer, because of their ability to form nitrosamines. However, after the discovery of mammalian endogenous nitric oxide (NO) generation and later that its oxidation products nitrate and nitrite can be recycled back to bioactive NO, a novel field of research has emerged that explores a potentially beneficial role of these anions in physiology, nutrition, and therapeutics. In our diet, vegetables are the major source of nitrate that can fuel a nitrate-nitrite-NO pathway. Herein we discuss the nutritional aspects of this pathway and what is presently known about the implications for human health. Expected final online publication date for the Annual Review of Nutrition Volume 33 is July 17, 2013. Please see for revised estimates.
    Annual Review of Nutrition 04/2013; · 9.16 Impact Factor
  • Mirco Govoni, Paola Tocchetti, Jon O Lundberg
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    ABSTRACT: Liver first-pass metabolism differs considerably among organic nitrates but little information exists on the mechanism of denitration of these compounds in hepatic tissue. The metabolism of nitrooxybutyl-esters of flurbiprofen and ferulic-acid, a class of organic nitrates with potential therapeutic implication in variety of different conditions, was investigated in comparison with glyceryl trinitrate (GTN) in human liver by a multiple approach, using a spontaneous metabolism-independent NO donor (NOC-5) as a reference tool. Nitrooxybutyl-esters were rapidly and quantitatively metabolized to their respective parent compounds and the organic nitrate moiety nitrooxybutyl-alcohol (NOBA). Differently from GTN which was rapidly and completely metabolized to nitrite, NOBA was slowly metabolized to nitrate. In contrast to the spontaneous NO donor NOC-5, NOBA and GTN did not generate detectable NO and failed to suppress the activity of cytochromeP450; an enzyme known to be inhibited by NO. The direct identification of NOBA following liver metabolism targets this compound as the functional organic nitrate metabolite of nitrooxybutyl-esters. Moreover the investigation of the pathways for denitration of NOBA and GTN suggests that organic nitrates are not primarily metabolized to NO in the liver but to different extents of nitrite or nitrate depending from their different chemical structure. It follows that cytochromeP450-dependent metabolism of concomitant drugs is not likely to be affected by oral co-administration of organic nitrates. However the first-pass may differently affect the pharmacological profile of organic nitrates in connection with the different extent of denitration and the distinct bioactive species generated and exported from the liver (nitrate or nitrite).
    Journal of Pharmacology and Experimental Therapeutics 04/2013; · 3.89 Impact Factor
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    ABSTRACT: Rats with adenine-induced chronic renal failure (A-CRF) develop metabolic and cardiovascular abnormalities resembling those in patients with chronic kidney disease. The aim of this study was to investigate the mechanisms of hypertension in this model and to assess aortic stiffness in vivo. Male Sprague-Dawley rats were equipped with radiotelemetry probes for arterial pressure recordings and received either chow containing adenine or normal control diet. At 7 to 11 weeks after study start, blood pressure responses to high NaCl (4%) diet and different pharmacological interventions were analyzed. Aortic pulse wave velocity was measured under isoflurane anesthesia. Baseline 24 h mean arterial pressure (MAP) was 101±10 and 119±9 mmHg in controls and A-CRF animals, respectively (P<0.01). After 5 days of high NaCl diet MAP had increased by 24±6 mmHg in A-CRF animals vs. 2±1 mmHg in controls (P<0.001). Candesartan (10 mg/kg by gavage) produced a more pronounced reduction of MAP in controls vs. A-CRF animals (-12±3 vs. -5±5 mmHg, P<0.05). Aortic pulse wave velocity was elevated in A-CRF rats (5.10±0.51 vs. 4.58±0.17 m/s, P<0.05). Plasma levels of creatinine were markedly elevated in A-CRF animals (259±46 vs. 31±2 µM, P<0.001) whereas plasma renin activity was suppressed (0.6±0.5 vs. 12.3±7.3 µg/L/h, P<0.001). In conclusion, hypertension in A-CRF animals is characterized by low plasma renin activity and is aggravated by high NaCl diet suggesting a pathogenic role for sodium retention and hypervolemia probably secondary to renal insufficiency. Additionally, aortic stiffness was elevated in A-CRF animals as indicated by increased aortic pulse wave velocity.
    AJP Regulatory Integrative and Comparative Physiology 03/2013; · 3.28 Impact Factor
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    ABSTRACT: Hydrogen sulfide (H2S), generated through various endogenous enzymatic and non-enzymatic pathways, is emerging as a regulator of physiological and pathological events throughout the body. Bacteria in the gastrointestinal tract also produce significant amounts of H2S that regulates microflora growth and virulence responses. However, the impact of the microbiota on host global H2S bioavailability and metabolism remain unknown. To address this question, we examined H2S bioavailability in its various forms (free, acid labile or bound sulfane sulfur), cystathionine gamma lyase (CSE) activity and cysteine levels in tissues from germ free versus conventionally housed mice. Free H2S levels were significantly reduced in plasma and gastrointestinal tissues of germ free mice. Bound sulfane sulfur levels were decreased by 50-80% in germ free mouse plasma, adipose and lung tissues. Tissue CSE activity was significantly reduced in many organs from germ free mice, whereas tissue cysteine levels were significantly elevated compared to conventional mice. These data reveal that the microbiota profoundly regulates systemic bioavailability and metabolism of H2S.
    Free Radical Biology & Medicine 03/2013; · 5.27 Impact Factor
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    ABSTRACT: AIM: Early life reduction in nephron number and chronic high salt intake cause development of renal and cardiovascular disease, which has been associated with oxidative stress and nitric oxide (NO) deficiency. We investigated the hypothesis that interventions stimulating NO signalling or reducing oxidative stress, may restore renal autoregulation, attenuate hypertension, and reduce renal and cardiovascular injuries following reduction in renal mass reduction and chronic high salt intake. METHODS: Male Sprague-Dawley rats were uninephrectomized (UNX) or sham-operated at 3-weeks of age and given either a normal-salt (NS) or high-salt (HS) diet. Effects on renal and cardiovascular functions were assessed in rats supplemented with substrate for NO synthase (L-Arg) or a superoxide dismutase mimetic (tempol). RESULTS: Rats with UNX+HS developed hypertension and displayed increased renal NADPH oxidase activity, elevated levels of oxidative stress markers in plasma and urine, and reduced cGMP in plasma. Histological analysis showed signs of cardiac and renal inflammation and fibrosis. These changes were linked with abnormal renal autoregulation, measured as a stronger tubuloglomerular feedback (TGF) response. Simultaneous treatment with L-Arg or tempol restored cGMP levels in plasma and increased markers of NO signalling in the kidney. This was associated with normalized TGF responses, attenuated hypertension, and reduced signs of histopathological changes in the kidney and in the heart. CONCLUSION: Reduction in nephron number during early life followed by chronic HS intake is associated with oxidative stress, impaired renal autoregulation and development of hypertension. Treatment strategies that increase NO bioavailability, or reduce levels of reactive oxygen species, were proven beneficial in this model of renal and cardiovascular disease. Acta Physiologica © 2013 Scandinavian Physiological Society.
    Acta Physiologica 02/2013; · 4.38 Impact Factor
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    ABSTRACT: Background Inorganic nitrate and nitrite have emerged as alternative substrates for nitric oxide (NO) generation in the gastrointestinal tract, and have shown to be protective against drug-induced gastric injury. The aim of this study was to investigate the preventive and therapeutic effects of nitrate and nitrite in a model of experimental colitis.Methods Colitis was induced in mice by administrating dextran sulfate sodium (DSS) with concurrent administration of nitrite (1 mM) or nitrate (10 mM) in the drinking water for 7 days. A therapeutic approach was also investigated by initiating nitrite treatment 3 days after DSS-induced colitis. Clinical and inflammatory markers were assessed and the colonic mucus thickness was measured in vivo. The effect of nitrite on wound healing was evaluated using colon epithelial cells.ResultsConcurrent administration of DSS and nitrite (1 mM) alleviated inflammation as determined by reduced disease activity index score (DAI) and increased colon length, while nitrate (10 mM) only reduced the DAI-score. Nitrite also displayed therapeutic effects by ameliorating established colonic inflammation with reduced colonic expression of iNOS and improving histopathology. DSS-induced decrease in colonic mucus thickness was completely prevented by nitrite administration. In addition, goblet cell abundance was lower by DSS treatment, but was increased by addition of nitrite. Further studies using colon epithelial cells revealed an NO-dependent improvement in wound healing with nitrite administration.Conclusion Nitrite exerts both preventive and therapeutic effects in colonic inflammation. The protective effects involve preservation of an intact adherent mucus layer and regulation of epithelial cell restitution.
    Redox Biology. 01/2013;
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    ABSTRACT: OBJECTIVE: Dietary nitrate is reduced to nitrite and nitric oxide ((•)NO) in the gut, producing reactive species able to nitrate proteins and lipids. We investigated intragastric production of (•)NO and nitrating agents in vivo by examining selective nitration of pepsinogen and pepsin. We further address the functional impact of nitration on peptic activity by evaluating the progression of secretagogue-induced ulcers. DESIGN: Pepsinogen nitration was assessed in healthy and diclofenac-induced ulcerated rat stomachs. Both groups were fed nitrite or water by oral gavage. Protein nitration was studied by immunofluorescence and immunoprecipitation. In parallel experiments, pentagastrin was administered to rats and nitrite was then instilled intragastrically. (•)NO levels were measured before and after nitrite administration by chemiluminescence. Macroscopic damage was assessed and nitrated pepsin was examined in the margin of ulcers. RESULTS: Protein nitration was detected physiologically in the stomach of healthy animals. Nitrite had a dual effect on intragastric nitration: overall nitration was decreased under physiological conditions but enhanced by acute inflammation. Pepsin and pepsinogen were also nitrated via a nitrite-dependent pathway. Nitration of both pepsin and its zymogen lead to decreased peptic activity in response to classical substrates (e.g. collagen). Under conditions of acute ulceration, nitrite-dependent pepsin nitration prevented the development of gastric ulcers. CONCLUSION: Dietary nitrite generates nitrating agents in the stomach in vivo, markedly decreasing peptic activity. Under inflammatory and ulcerogenic conditions pepsin nitration attenuates the progression of gastric ulceration. These results suggest that dietary nitrite-dependent nitration of pepsin may have a novel anti-ulcerogenic effect in vivo.
    Free Radical Biology & Medicine 12/2012; · 5.27 Impact Factor
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    ABSTRACT: Circulating nitrate (NO(3)(-)), derived from dietary sources or endogenous nitric oxide production, is extracted from blood by the salivary glands, accumulates in saliva and is then reduced to nitrite (NO(2)(-)) by the oral microflora. This process has historically been viewed as harmful, since nitrite can promote formation of potentially carcinogenic N-nitrosamines. More recent research, however, suggests that nitrite can also serve as a precursor for systemic generation of vasodilatory nitric oxide, and exogenous administration of nitrate reduces blood pressure in humans. However, whether oral nitrate-reducing bacteria participate in 'setting' blood pressure is unknown. We investigated whether suppression of the oral microflora affects systemic nitrite levels and hence blood pressure in healthy individuals. We measured blood pressure (clinic, home and 24h ambulatory) in 19 healthy volunteers during an initial 7 day control period followed by a 7 day treatment period with a chlorhexidine-based antiseptic mouthwash. Oral nitrate-reducing capacity and nitrite levels were measured after each study period. Antiseptic mouthwash treatment reduced oral nitrite production by 90% (p<0.001) and plasma nitrite levels by 25% (p=0.001) compared to the control period. Systolic and diastolic blood pressure increased by 2-3.5mmHg; increases correlated to decrease in circulating nitrite concentrations (r(2)=0.56, p=0.002). The blood pressure effect appeared within one day of disruption of the oral microflora and was sustained during the 7 day mouthwash intervention. These results suggest that the recycling of endogenous nitrate by oral bacteria plays an important role in determination of plasma nitrite levels and thereby in the physiological control of blood pressure.
    Free Radical Biology & Medicine 11/2012; · 5.27 Impact Factor
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    ABSTRACT: Inorganic nitrate has been shown to reduce oxygen cost during exercise. Since the nitrate-nitrite-NO pathway is facilitated during hypoxia, we investigated the effects of dietary nitrate on oxygen consumption and cardiovascular responses during apnea. These variables were measured in two randomized, double-blind, placebo-controlled, crossover protocols at rest and ergometer exercise in competitive breath-hold divers. Subjects held their breath for predetermined times along with maximum effort apneas after two separate 3-day periods with supplementation of potassium nitrate/placebo. In contrast to our hypothesis, nitrate supplementation led to lower arterial oxygen saturation (SaO(2), 77±3%) compared to placebo (80±2%) during static apnea, along with lower end-tidal fraction of oxygen (FETO(2)) after 4min of apnea (nitrate 6.9±0.4% vs. placebo 7.6±0.4%). Maximum apnea duration was shorter after nitrate (329±13s) compared to placebo (344±13s). During cycle ergometry nitrate had no effect on SaO(2), FETO(2) or maximum apnea duration. The negative effects of inorganic nitrate during static apnea may be explained by an attenuated diving response.
    Respiratory Physiology & Neurobiology 10/2012; · 2.05 Impact Factor
  • Sara Borniquel, Cecilia Jädert, Jon O Lundberg
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    ABSTRACT: A central event in inflammatory bowel disease is the disruption of the mucosal homeostasis. Trefoil peptides [(TFF)] are emerging as key mediators in the defense and repair of the gastrointestinal mucosa. Here, we demonstrate induction of TFF by CLA with therapeutic antiinflammatory effects in a mouse model of inflammatory bowel disease. SW480 cells were treated with linoleic acid or CLA (0-2.5 μmol/L) in the absence or presence of the PPARγ inhibitor GW9662. Cells treated with CLA showed an upregulation of the intestinal trefoil factor, which was prevented by pretreatment with GW9662. Dextran sulfate sodium (2%) was used to induce colitis in mice and they were simultaneously fed with a standard or a CLA-supplemented (100 mg ⋅ kg(-1) ⋅ d(-1)) diet for 7 d. The CLA-enriched diet prevented the colon shortening induced by DSS and markedly reduced the disease activity index and the colonic expression of inducible NO synthase and NF-κB. Immunohistochemistry revealed an increase in PPARγ and TFF3 expression after CLA administration. Altogether, these results indicate that dietary CLA protects against DSS-induced colitis in a process involving induction of PPARγ and TFF3.
    Journal of Nutrition 10/2012; · 4.20 Impact Factor
  • Eddie Weitzberg, Jon Lundberg
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    ABSTRACT: Revascularization is an adaptive repair mechanism that restores blood flow to undersupplied ischemic tissue. Nitric oxide plays an important role in this process. Whether dietary nitrate, serially reduced to nitrite by commensal bacteria in the oral cavity and subsequently to nitric oxide and other nitrogen oxides, enhances ischemia-induced remodeling of the vascular network is not known. Mice were treated with either nitrate (1 g/L sodium nitrate in drinking water) or sodium chloride (control) for 14 days. At day 7, unilateral hind-limb surgery with excision of the left femoral artery was conducted. Blood flow was determined by laser Doppler. Capillary density, myoblast apoptosis, mobilization of CD34(+)/Flk-1(+), migration of bone marrow-derived CD31(+)/CD45(-), plasma S-nitrosothiols, nitrite, and skeletal tissue cGMP levels were assessed. Enhanced green fluorescence protein transgenic mice were used for bone marrow transplantation. Dietary nitrate increased plasma S-nitrosothiols and nitrite, enhanced revascularization, increased mobilization of CD34(+)/Flk-1(+) and migration of bone marrow-derived CD31(+)/CD45(-) cells to the site of ischemia, and attenuated apoptosis of potentially regenerative myoblasts in chronically ischemic tissue. The regenerative effects of nitrate treatment were abolished by eradication of the nitrate-reducing bacteria in the oral cavity through the use of an antiseptic mouthwash. Long-term dietary nitrate supplementation may represent a novel nutrition-based strategy to enhance ischemia-induced revascularization.
    Circulation 09/2012; 126(16):1983-92. · 15.20 Impact Factor
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    ABSTRACT: Endogenous nitric oxide (NO) generated from l-arginine by NO synthase regulates mitochondrial function by binding to cytochrome c oxidase in competition with oxygen. This interaction can elicit a variety of intracellular signaling events of both physiological and pathophysiological significance. Recent lines of research demonstrate that inorganic nitrate and nitrite, derived from oxidized NO or from the diet, are metabolized in vivo to form NO and other bioactive nitrogen oxides with intriguing effects on cellular energetics and cytoprotection. Here we discuss the latest advances in our understanding of the roles of nitrate, nitrite, and NO in the modulation of mitochondrial function, with a particular focus on dietary nitrate and exercise.
    Free Radical Biology & Medicine 08/2012; 53(10):1919-1928. · 5.27 Impact Factor
  • Circulation Journal 08/2012; · 3.58 Impact Factor

Publication Stats

6k Citations
1,162.54 Total Impact Points


  • 1994–2014
    • Karolinska Institutet
      • Department of Physiology and Pharmacology
      Solna, Stockholm, Sweden
  • 2007–2013
    • Uppsala University
      • Department of Medical Cell Biology
      Uppsala, Uppsala, Sweden
  • 1998–2013
    • Karolinska University Hospital
      • • Department of Cardiology
      • • Department of Urology
      • • Department of Pediatric Anesthesiology and Intensive Care
      • • Department of Thoracic Surgery
      Stockholm, Stockholm, Sweden
  • 2012
    • Universitätsklinikum Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2007–2012
    • University of Coimbra
      • • Centro de Neurociências e Biologia Celular (CNC)
      • • Faculdade de Farmácia
      Coimbra, Distrito de Coimbra, Portugal
  • 2010
    • University of Texas Health Science Center at Houston
      Houston, Texas, United States
  • 2009
    • Utrecht University
      Utrecht, Utrecht, Netherlands
  • 2008
    • Second University of Naples
      Caserta, Campania, Italy
  • 2006
    • Stockholm University
      • Department of Geological Sciences
      Stockholm, Stockholm, Sweden
  • 2005
    • National Heart, Lung, and Blood Institute
      • Pulmonary & Vascular Medicine Branch
      Maryland, United States
  • 2004
    • Sahlgrenska University Hospital
      Goeteborg, Västra Götaland, Sweden