Abstract 18112: SIRT3-AMPK Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes PH-HFpEF
Background: Pulmonary hypertension in heart failure with preserved ejection fraction (PH-HFpEF) is an increasingly common cause of PH and a newly recognized clinical complication of metabolic syndrome. To date, no animal model of PH-HFpEF associated with metabolic syndrome has been developed and no specific therapy has yet been shown to favorably affect patients with PH-HFpEF.
Methods and Results: We first developed a relevant animal model of PH-HFpEF by injecting the VEGF receptor blocker, SU5416, in a genetic model of obese, diabetic, insulin-resistant, and spontaneously hypertensive rats (ZSF1). Our data showed that SU5416/ZSF1 rats resulted in enhanced RVPSP and was accompanied by elevated LVEDP, preserved LV EF, and both LV and RV enlargement. Next, the therapeutic and mechanistic effects of nitrite and an anti-diabetic drug, metformin, on metabolic syndrome and PH-HFpEF were explored. We found that chronic nitrite treatment significantly improved hyperglycemia in obese ZSF1 rats. Nitrite administration had no effect on plasma insulin levels and the insulin-dependent signaling pathway, but it significantly increased AMPK phosphorylation and membrane translocation of GLUT4, the key regulators of glucose uptake in skeletal muscle. In addition, sirtuin-3 (SIRT3), a major mitochondrial deacetylase, was also upregulated and activated by nitrite in rat skeletal muscles. Moreover, knockdown of SIRT3 expression in human skeletal muscle cells resulted in impaired AMPK activation and glucose uptake. Finally, in our newly developed PH-HFpEF model (SU5416/ZSF1), we found that both oral nitrite and oral metformin therapies normalize PH-HFpEF in terms of hemodynamic benefits, reduced pulmonary vascular remodeling, and improved hyperglycemia via SIRT3-AMPK activation.
Conclusions: Our “two-hit” model of PH-HFpEF provides evidence for an interaction between metabolic syndrome and pulmonary endothelial injury to the subsequent development of PH-
HFpEF: Our observations also indicate that chronic oral nitrite and metformin therapies limited PH-HFpEF through SIRT3-AMPK-mediated signaling events, providing new therapeutic strategies in the treatment of patients with PH-HFpEF.
Author Disclosures: Y. Lai: Ownership Interest; Modest; Co-inventor on U.S. government patent for nitrite salts for the treatment of cardiovascular indications, licensed and held by the NIH. Consultant/Advisory Board; Modest; Bayer consultant/advisory board, not to exceed $10,000 in calendar year, plus travel (travel total $9,941 for past year). Consultant/Advisory Board; Significant; Bayer Corporation funding. D.M. Tabima: None. J.J. Dube: None. D.A. Goncharov: None. E.A. Goncharova: None. S.P. Tofovic: None. A.L. Mora: None. M.T. Gladwin: Consultant/Advisory Board; Modest; Bayer consultant/advisory board, not to exceed $10,000 in calendar year, plus travel (travel total $9,941 for past year). Other; Modest; Co-inventor on U.S. government patent for nitrite salts for the treatment of cardiovascular indications, licensed and held by the NIH. Royalities for past year were approximately $800. Research Grant; Significant; NIH and NHLBI - P01 and R01 grant support to University of Pittsburgh (not to Dr. Gladwin), HCWP and ITXM Institute funding to University of Pittsburgh (not to Dr. Gladwin), Bayer Corporation funding (Ana Mora PI, funds to University of Pittsburgh).
- © 2014 by American Heart Association, Inc.