15 February 2020 by Charly Lai

Skeletal muscle LKB1/SIRT3-AMPK-GLUT4 activation by treprostinil and metformin normalizes hyperglycemia and improves cardiac function in Pulmonary Hypertension Associated with Heart Failure with Preserved Ejection Fraction (PH-HFpEF)

Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF; Group 2) is the most common cause of PH worldwide, but has no proven drug therapy at present. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable and long-lasting prostacyclin analog, treprostinil, is an effective and widely used FDA-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF.

Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet (HFD) and to SU5416/Obese ZSF1 rats, a model which is created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In HFD-exposed mice, chronic treatment with treprostinil prevented hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin - the first-line drug for type 2 diabetes; the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio (PAAT/ET) and tricuspid annular plane systolic excursion (TAPSE) with robust activation of skeletal muscle LKB1/SIRT3-AMPK-GLUT4 signaling.

Our data suggest a potential role of treprostinil as a preventative treatment for mild metabolic syndrome-associated PH-HFpEF. Our data also suggest that combined treatment with treprostinil and metformin may be a potential effective therapy for a more severe disease.

About the author


profile picture of Charly Lai

Charly Lai

Assistant Professor of Medicine

Indiana University School of Medicine

United States

Key Contributors

Longfei Wang, Gunner Halliday, Joshua R. Huot, Taijyu Satoh, Jeff J. Baust, Jian Hu, Amanda Fisher, Rebecca R. Vanderpool, Robert V. Considine, Andrea Bonetto, Jiangning Tan, Timothy N. Bachman, Andrea Sebastiani, Ana L. Mora, Mark T. Gladwin and Yen-Chun Lai Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh; The Third Xiangya Hospital, Central South University; Changsha, Hunan, China; Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine; Department of Surgery, Indiana University School of Medicine; Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Division of Translational and Regenerative Medicine, University of Arizona; Division of Endocrinology, Indiana University School of Medicine; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh.


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