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Circulation. 2016 Feb 23;133(8):717-31. doi: 10.1161/CIRCULATIONAHA.115.018935. Epub 2016 Jan 26.

SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.

Author information

1
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 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.).
2
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 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.

Abstract

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.

KEYWORDS:

AMP-activated protein kinases; SIRT3 protein; heart failure; hypertension, pulmonary; metabolic syndrome

PMID:
26813102
PMCID:
PMC4766041
DOI:
10.1161/CIRCULATIONAHA.115.018935
[Indexed for MEDLINE]
Free PMC Article

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