Abstract 15694: Roles of Nitrite and Metformin in Severe Pulmonary Arterial Hypertension (PAH) and Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction (PH-HFpEF)
Background: PAH (Group I) is a disease of the small pulmonary arteries, characterized by vasoconstriction, vascular proliferation and remodeling. PH-HFpEF (Group II) is known to occur secondary to the LV diastolic dysfunction and is recognized as a clinical complication of metabolic syndrome, with no currently approved therapies. Since the use of conventional therapies for PAH in PH-HFpEF patients is often ineffective, targeting both pulmonary vascular disease and metabolic disorders appears to be a key strategy for the treatment of PH-HFpEF. We, as well as others, have reported that nitrite exhibits therapeutic efficacy in moderate PAH models and improves glucose metabolism. In addition, metformin, the canonical AMPK activator and the first-line anti-diabetic drug, has been found to prevent the development of moderate PAH. In this work, we examined the effects of nitrite and metformin in PH-HFpEF, and compared their effects in severe PAH.
Methods and Results: Nitrite (100mg/L) and metformin (300mg/kg) were given in drinking water to rats with Su5416/hypoxia-induced severe PAH or to rats with Su5416/metabolic syndrome-induced PH-HFpEF for 6 and 14 weeks, respectively. In the PH-HFpEF rats, our data showed that both nitrite and metformin treatments reduced pulmonary pressures and pathological vascular remodeling and limited hyperglycemia, which correlated with increased SIRT3-AMPK activation in skeletal muscles and AMPK activation in pulmonary vessels. Similar protective effect of nitrite was also observed in Su5416/hypoxia rats, together with increased activation of SIRT3 and AMPK in skeletal muscles. However, metformin failed to reduce pulmonary pressures and vascular remodeling in Su5416/hypoxia rats, with unchanged activation levels of SIRT3 and AMPK, suggesting metformin may favorably affect PH only in the presence of metabolic disorders. In addition, the AMPK agonist AICAR was found incapable of limiting PAH in Su5416/hypoxia rats.
Conclusions: Our findings indicate that oral nitrite treatment limits PH-HFpEF, as well as PAH, while metformin treatment more preferentially improves PH-HFpEF. Our findings also indicate that activation of SIRT3-AMPK may represent a potential therapeutic route in the treatment of both PAH and PH-HFpEF.
Author Disclosures: Y. Lai: Consultant/Advisory Board; Modest; Mark Gladwin. D. Tabima: None. R. Vanderpool: None. J. Hu: None. D. Goncharov: None. E. Goncharova: None. S. Tofovic: None. A. Mora: None. M. Gladwin: Consultant/Advisory Board; Modest; Bayer consultant/advisory board.
- © 2015 by American Heart Association, Inc.