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

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 eNOS null mice, and multiple studies have reported that both nitrate and its active metabolite, nitrite, have therapeutic activity in pre-clinical models of PH. Methods and Results In order to evaluate the efficacy and mechanism of nitrite in metabolic syndrome associated with PH-HFpEF, we developed a “two-hit” PH-HFpEF model in rats with multiple features of metabolic syndrome due to double leptin receptor defect (obese ZSF1) with the combined treatment of VEGF 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, as well as in SIRT3 knockout mice fed a high-fat diet. 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 AMPK. 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 AMPK. 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.

The Effects of Metformin on Obesity-Induced Dysfunctional Retinas

“…Interestingly, the retinas from these HFD+Met mice had an apparent up-regulation of total AMPK and pAMPK compared to the controls, which indicated that metformin might have a direct effect on AMPK in the neural retina, as metformin is known to up-regulate the expression and activation of AMPK in the kidney, 36 adipose tissue, 13,37 and heart. 38 …”

“…51 Metformin is known to up-regulate the expression and activation of AMPK in the kidney, 36 adipose tissue, 13,37 and heart. 38 Hence, the effects of metformin on pAKT could be a downstream effect from its activation of AMPK-dependent signaling.…”

Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction

“…More recent work has demonstrated that acute IV administration of nitrite improves exercise capacity in patients with HFpEF, a group at high risk for secondary (Group 2) PH (22). In a recent study by our group, chronic therapy with oral nitrite improved PH in a rat model of severe metabolic syndrome and PH associated with HFpEF (PHHFpEF) (23). We therefore sought to evaluate in a phase IIa safety and efficacy trial the acute effects of an inhaled formulation of nitrite on cardiopulmonary hemodynamics in patients with PH-HFpEF as compared with WHO Group 1 PAH or Group 3 PH.…”

Letter by Carlström and Lundberg Regarding Article, “SIRT3-AMP–Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction”

“…We read with interest the article by Lai and coworkers 1 published in Circulation about the favorable cardiovascular and metabolic effects of inorganic nitrite and metformin in patients with pulmonary hypertension in heart failure with preserved ejection fraction. Accumulating studies have demonstrated the therapeutic effects of stimulating the nitrate-nitrite-nitric oxide (NO) pathway in renal, cardiovascular, and metabolic disorders.…”