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.
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Obesity, hyperlipidemia, and systemic hypertension are common risk factors for Group I PAH as well as Group II PH and are also a feature of HIV infection.
“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]
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.
“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]
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- 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 › 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.
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