The DOI matches its Crossref record; 74 of the 74 references it cites were found in a registry or an index.
SIRT3-AMP-activated protein kinase activation by nitrite and metformin improves hyperglycemia and normalizes pulmonary hypertension associated with heart failure with preserved ejection fraction
Open accessAbstract
BACKGROUND: Pulmonary 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 RESULTS: To 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. CONCLUSIONS: These 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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“For example, obesity, hyperlipidemia, and systemic hypertension are common risk factors for Group I PAH as well as Group II (secondary to left-sided heart failure or PH-heart failure with preserved ejection fraction, HFpEF)[12,15,16], and are also a feature of HIV infection[17,18].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [15]
In the citing paper
“Delivered via intravenous, inhaled, or oral routes, nitrite reduces pulmonary and right heart pressures and prevents or reverses characteristic vascular remodeling and right ventricular hypertrophy (RVH) in several animal models of PAH[15,117,143,146–149].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [15]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
AMPK: a nutrient and energy sensor that maintains energy homeostasis
Hardie, D. G., Ross, F. A., & Hawley, S. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3311 · Cited by 4,602
Hawley, S. A., Pan, D. A., Mustard, K. J., Ross, L., Bain, J., Edelman, A. M., Frenguelli, B. G., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.009 · Cited by 1,589
Giaid, A., & Saleh, D. M. (1995) · New England Journal of Medicine · doi:10.1056/nejm199507273330403 · Cited by 1,366
Hawley, S. A., Davison, M., Woods, A., Davies, S. P., Beri, R. K., Carling, D., & Hardie, D. G. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.44.27879 · Cited by 1,264
Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation
Lombard, D. B., Alt, F. W., Cheng, H.-L., Bunkenborg, J., Streeper, R. S., Mostoslavsky, R., Kim, J., Yancopoulos, G., Valenzuela, D., Murphy, A., et al. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01636-07 · Cited by 1,216
Adiponectin and Metabolic Syndrome
Matsuzawa, Y., Funahashi, T., Kihara, S., & Shimomura, I. (2003) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000099786.99623.ef · Cited by 1,203
Webb, A. J., Patel, N., Loukogeorgakis, S., Okorie, M., Aboud, Z., Misra, S., Rashid, R., Miall, P., Deanfield, J., Benjamin, N., et al. (2008) · Hypertension · doi:10.1161/hypertensionaha.107.103523 · Cited by 1,078
The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism
Koo, S., Flechner, L., Qi, L., Zhang, X., Screaton, R. A., Jeffries, S., Hedrick, S. A., Xu, W., Boussouar, F., Brindle, P. K., et al. (2005) · Nature · doi:10.1038/nature03967 · Cited by 1,026
Taraseviciene‐Stewart, L., Kasahara, Y., Alger, L., Hirth, P., Mahon, G. M., Waltenberger, J. L., Voelkel, N. F., & Tuder, R. M. (2001) · The FASEB Journal · doi:10.1096/fj.00-0343com · Cited by 835
Hirschey, M. D., Shimazu, T., Jing, E., Grueter, C. A., Collins, A. M., Aouizerat, B., Stančáková, A., Goetzman, E., Lam, M. M., Schwer, B., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.07.019 · Cited by 787
Flagged first, then by citations
Research works printed but not linked: 2
- 10.1267/THRO04080413 · DOI
- Pflieger A, Potus F, Malenfant S, Breuils-Bonnet S, Provencher S, Bonnet S. Skeletal muscle metabolism defect in human pulmonary arterial hypertension. Am J Respir Crit Care Med. 2014;189:A2622.
Cited by
Sorted by citations
Obokata, M., Reddy, Y. N. V., Pislaru, S. V., Melenovsky, V., & Borlaug, B. A. (2017) · Circulation · doi:10.1161/circulationaha.116.026807 · Cited by 1,179
Nitric oxide signaling in health and disease
Lundberg, J. O., & Weitzberg, E. (2022) · Cell · doi:10.1016/j.cell.2022.06.010 · Cited by 879
Shah, S. J., Borlaug, B. A., Kitzman, D. W., McCulloch, A. D., Blaxall, B. C., Agarwal, R., Chirinos, J. A., Collins, S., Deo, R. C., Gladwin, M. T., et al. (2020) · Circulation · doi:10.1161/circulationaha.119.041886 · Cited by 436
Cellular and molecular pathobiology of heart failure with preserved ejection fraction
Mishra, S., & Kass, D. A. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-020-00480-6 · Cited by 437
Metabolic Effects of Dietary Nitrate in Health and Disease
Lundberg, J. O., Carlström, M., & Weitzberg, E. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.06.007 · Cited by 374
Metadata
- Authors
- Lai, Y.-C., Tabima, D. M., Dube, J. J., Hughan, K. S., Vanderpool, R. R., Goncharov, D. A., St. Croix, C. M., Garcia-Ocaña, A., Goncharova, E. A., Tofovic, S. P., Mora, A. L., & Gladwin, M. T.
- Affiliations
- University of Pittsburgh (US)
- From 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...
- ORCID
- Venue
- Circulation
- Published
- 2016-02-23
- Volume
- 133
- Issue
- 8
- Pages
- 717-731
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC4766041
- OpenAlex
- W2274562896
- Cited by
- 270
- References
- 74
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 26 · 2023: 25 · 2022: 26 · 2021: 24 · 2020: 31 · 2019: 21 · 2018: 37 · 2017: 26 · 2016: 17
- FWCI
- 30.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- University of Pittsburgh (UL1TR000005, UL1RR024153, RR024153)
- Hemophilia Center of Western Pennsylvania (T32 HL110849)
- National Institutes of Health (5t32dk007729-24, UL1TR000005, UL1-TR- 000005, RR024153, TR000005)
- National Heart, Lung, and Blood Institute (R01HL096973, P01HL103455, K23HL124051, HL110849, R01HL113178, R01HL098032, T32HL110849)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK-007729, P30DK020541)
- National Center for Research Resources (UL1RR024153)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD052892)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Keywords
- pulmonary hypertension, heart failure with preserved ejection fraction, nitrite, nitrate, SIRT3, AMPK, metformin, hyperglycemia, metabolic syndrome, skeletal muscle, GLUT4, leptin receptor, SU5416, vascular remodeling, animal models
- MeSH terms
- Animals, Cells, Cultured, Enzyme Activation, Heart Failure, Humans, Hyperglycemia, Hypertension, Pulmonary, Male, Metformin, Rats, Zucker, Sodium Nitrite, Stroke Volume, Mice, Knockout, Muscle, Skeletal, Mice, Rats, AMP-Activated Protein Kinases, Sirtuin 3, Mice, 129 Strain
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
