ArticleCirculation2016
SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.
Registry-linked trialOpen access · bronzeAbstract read
In one paragraph
Article in Circulation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01431313 (A Dose Escalation Study to Evaluate the Effect of Inhaled Nitrite on Cardiopulmonary Hemodynamics in Subjects With Pulmonary Hypertension), which is not on this map. Cited by 160 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
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160citing papers in PubMed, 1 pooled it
17.6field-weighted citation impact, top 1% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Dose Escalation Study to Evaluate the Effect of Inhaled Nitrite on Cardiopulmonary Hemodynamics in Subjects With Pulmonary Hypertension
Who cites it
160 citing papers in PubMed, 1 synthesis or guideline pooled it, 268 citations in OpenAlex.
- Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement.American journal of respiratory and critical care medicine · 2018Guideline
- Inorganic Nitrate in Angina Study: A Randomized Double-Blind Placebo-Controlled Trial.Journal of the American Heart Association · 2017Trial
- Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction.JCI insight · 2016Trial
- Inhaled Sodium Nitrite Improves Rest and Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction.Circulation research · 2016Trial
- Pitfalls of Therapies Targeting the Nitric Oxide Signaling Pathway in Heart Failure With Preserved Ejection Fraction.Journal of cardiovascular pharmacology · 2026Review
- Post-translational modifications of mitochondrion-related proteins: integrative orchestrators of cell fate networks in cardiovascular disease.Cell communication and signaling : CCS · 2026Review
- Association of Antidiabetic Medication Classes With Survival Outcomes in Pulmonary Hypertension Patients With Diabetes.Pulmonary circulation · 2026Article
- Decreased AMP-kinase function in pulmonary artery smooth muscle cells contributes to pulmonary artery remodeling in persistent pulmonary hypertension of the newborn.American journal of physiology. Lung cellular and molecular physiology · 2026Article
- Metformin attenuates HSV-1-induced neuropathic pain by restoring Sirt3-mediated mitophagy.Cell communication and signaling : CCS · 2026Article
- The association between dietary intakes of nitrate and nitrite and odds of metabolic syndrome and its component in adults.Scientific reports · 2026Article
- Prevalence and risk factors of pulmonary hypertension in maintenance hemodialysis patients based on echocardiography.Medicine · 2026Article
- Excitation-contraction coupling, cardiomyocyte electrophysiology, and transcriptome profiles in two HFpEF murine models: etiology and sex-dependent differences.American journal of physiology. Heart and circulatory physiology · 2026Article
- Trigonelline Improves Metabolism and Cardiac Function of HFpEF Mice Via Gut Microbiome Alterations-Mediated AMPK Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Systemic Interactions in HFpEF: A Multiorgan Perspective on Pathways and Therapeutic Targets.Journal of cardiovascular translational research · 2025Review
- Targeting SIRT3 to Ameliorate Diabetic Cardiomyopathy: Progress in Mechanistic Research and Prospects for Clinical Translation.Journal of diabetes · 2025Review
- The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction: A Novel Framework to Explain Pathogenesis and Guide Treatment.Journal of the American College of Cardiology · 2025Review
- From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin.International journal of molecular sciences · 2025Review
- What Is Cardiometabolic HFpEF and How Can We Study it Preclinically?JACC. Basic to translational science · 2025Review
- Cationic microbubble loading hSIRT3 and hTIMP3 optimize cardiac-targeted delivery and myocardial protection in the porcine MI/R model.Materials today. Bio · 2025Article
- Prevention of Metabolic Impairment by Dietary Nitrate in Overweight Male Mice Improves Stroke Outcome.Nutrients · 2025Article
100 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 2 institutions in 1 country.
Yen-Chun LaiFrom Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
Diana M TabimaFrom Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
John J DubeFrom Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
Kara S HughanFrom Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
Rebecca R VanderpoolFrom Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
Dmitry A GoncharovFrom Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
Claudette M St CroixFrom Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
Adolfo Garcia-OcañaFrom Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
Elena A GoncharovaFrom Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
Stevan P TofovicFrom Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
Ana L MoraFrom Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.).
Mark T GladwinFrom Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (Y.-C.L., D.M.T., K.S.H., R.R.V., D.A.G., E.A.G., S.P.T., A.L.M., M.T.G.); Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA (J.J.D.); Division of Pediatric Endocrinology, Metabolism and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA (K.S.H.); Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (C.M.St.C.); Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY (A.G.-O.); and Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (E.A.G., S.P.T., A.L.M., M.T.G.). gladwinmt@upmc.edu.
Icahn School of Medicine at Mount Sinai · USUniversity of Pittsburgh · US
Funding
UNIVERSITY OF PITTSBURGH CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE: BPCAUL1RR024153 · NCRR · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI REIS, STEVEN E · 2006 to 2011
$73.9MUniversity of Pittsburgh Clinical and Translational Science InstituteUL1TR000005 · NCATS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI REIS, STEVEN E · 2012 to 2015
$50.8MTranslational Research CoreP30DK020541 · NIDDK · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI Shuibing Chen · 2015 to 2026
$27.7MVascular Subphenotypes of Lung DiseaseP01HL103455 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI MORA, ANA LUCIA · 2011 to 2020
$26.1MStorage Lesion in Banked Blood Due to Disruption of Nitric Oxide HomeostasisR01HL098032 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Mark T Gladwin · 2009 to 2026
$12.5MMolecular Basis of Pediatric DiseaseK12HD052892 · NICHD · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI TERENCE S. DERMODY · 2007 to 2026
$6.5MTranslational Pulmonary Vascular BiologyT32HL110849 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Sruti Shiva · 2012 to 2026
$5.0MRESEARCH TRAINING IN PEDIATRIC ENDOCRINOLOGY &DIABETEST32DK007729 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI MUZUMDAR, RADHIKA HIREN · 1995 to 2020
$3.3MTSC2 Signaling in Pulmonary Arterial HypertensionR01HL113178 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GONCHAROVA, ELENA · 2012 to 2021
$3.1MMyoglobin as a Nitrite Reductase that Regulates Hypoxic Cardiac NO SignalingR01HL096973 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GLADWIN, MARK T, SHIVA, SRUTI · 2010 to 2013
$1.5MNitrite Modulation of Hypertension, Platelet Activation and Endothelial and Mitochondrial FunctionK23HL124051 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI HUGHAN, KARA S. · 2015 to 2017
$471kNCATS NIH HHS UL1 TR000005NCRR NIH HHS UL1 RR024153NHLBI NIH HHS 2P01HL103455NHLBI NIH HHS 2R01HL098032NHLBI NIH HHS K23 HL124051NHLBI NIH HHS P01 HL103455NHLBI NIH HHS R01 HL096973NHLBI NIH HHS R01HL096973NHLBI NIH HHS R01 HL098032NHLBI NIH HHS R01 HL113178NHLBI NIH HHS R01HL113178NHLBI NIH HHS T32 HL110849NICHD NIH HHS 5K12-HD052892NICHD NIH HHS K12 HD052892NIDDK NIH HHS P30 DK020541NIDDK NIH HHS T32 DK007729
Abstract
backgroundPulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is an increasingly recognized clinical complication of metabolic syndrome. No adequate animal model of PH-HFpEF is available, and no effective therapies have been identified to date. A recent study suggested that dietary nitrate improves insulin resistance in endothelial nitric oxide synthase null mice, and multiple studies have reported that both nitrate and its active metabolite, nitrite, have therapeutic activity in preclinical models of pulmonary hypertension. METHODS AND
resultsTo evaluate the efficacy and mechanism of nitrite in metabolic syndrome associated with PH-HFpEF, we developed a 2-hit PH-HFpEF model in rats with multiple features of metabolic syndrome attributable to double-leptin receptor defect (obese ZSF1) with the combined treatment of vascular endothelial growth factor receptor blocker SU5416. Chronic oral nitrite treatment improved hyperglycemia in obese ZSF1 rats by a process that requires skeletal muscle SIRT3-AMPK-GLUT4 signaling. The glucose-lowering effect of nitrite was abolished in SIRT3-deficient human skeletal muscle cells, and in SIRT3 knockout mice fed a high-fat diet, as well. Skeletal muscle biopsies from humans with metabolic syndrome after 12 weeks of oral sodium nitrite and nitrate treatment (IND#115926) displayed increased activation of SIRT3 and AMP-activated protein kinase. Finally, early treatments with nitrite and metformin at the time of SU5416 injection reduced pulmonary pressures and vascular remodeling in the PH-HFpEF model with robust activation of skeletal muscle SIRT3 and AMP-activated protein kinase.
conclusionsThese studies validate a rodent model of metabolic syndrome and PH-HFpEF, suggesting a potential role of nitrite and metformin as a preventative treatment for this disease.
Indexed as
AMP-Activated Protein KinasesAnimalsCells, CulturedEnzyme ActivationHeart FailureHumansHyperglycemiaHypertension, PulmonaryMaleMetforminMiceMice, 129 StrainMice, KnockoutMuscle, SkeletalRatsRats, ZuckerAMP-Activated Protein KinasesMetforminSirt3 protein, mouseSirtuin 3Sodium NitriteAMP-activated protein kinasesheart failurehypertension, pulmonarymetabolic syndromeSIRT3 protein
Identifiers
What Socratic holds
Texttitle and abstract
LicenceTDM
Read underepoch 390
Registered trials
NCT01431313ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.