Monte S Willis1,2,3, Amro Ilaiwy4,5, Megan D Montgomery6, Paul C Simpson6, Brian C Jensen1,7. 1. McAllister Heart Institute, University of North Carolina, Chapel Hill, NC USA. 2. Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC USA. 3. Department of Pharmacology, University of North Carolina, Chapel Hill, NC USA. 4. Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA. 5. Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA. 6. VA Medical Center and University of California, San Francisco, CA, USA. 7. Department of Internal Medicine, Division of Cardiology University of North Carolina, Chapel Hill, NC, USA.
Abstract
INTRODUCTION: Alpha-1-adrenergic receptors (α1-ARs) are G-protein coupled receptors (GPCRs) with three highly homologous subtypes (α1A, α1B, and α1D). Of these three subtypes, only the α1A and α1B are expressed in the heart. Multiple pre-clinical models of heart injury demonstrate cardioprotective roles for the α1A. Non-selective α1-AR activation promotes glycolysis in the heart, but the functional α1-AR subtype and broader metabolic effects have not been studied. OBJECTIVES: Given the high metabolic demands of the heart and previous evidence indicating benefit from α1A activation, we chose to investigate the effects of α1A activation on the cardiac metabolome in vivo. METHODS: Mice were treated for one week with a low, subpressor dose of A61603, a highly selective and potent α1A agonist. Cardiac tissue and serum were analyzed using a non-targeted metabolomics approach. RESULTS: We identified previously unrecognized metabolic responses to α1A activation, most notably broad reduction in the abundance of polyunsaturated fatty acids (PUFAs) and endocannabinoids (ECs). CONCLUSION: Given the well characterized roles of PUFAs and ECs in inflammatory pathways, these findings suggest a possible role for cardiac α1A-ARs in the regulation of inflammation and may offer novel insight into the mechanisms underlying the cardioprotective benefit of selective pharmacologic α1A activation.
INTRODUCTION: Alpha-1-adrenergic receptors (α1-ARs) are G-protein coupled receptors (GPCRs) with three highly homologous subtypes (α1A, α1B, and α1D). Of these three subtypes, only the α1A and α1B are expressed in the heart. Multiple pre-clinical models of heart injury demonstrate cardioprotective roles for the α1A. Non-selective α1-AR activation promotes glycolysis in the heart, but the functional α1-AR subtype and broader metabolic effects have not been studied. OBJECTIVES: Given the high metabolic demands of the heart and previous evidence indicating benefit from α1A activation, we chose to investigate the effects of α1A activation on the cardiac metabolome in vivo. METHODS:Mice were treated for one week with a low, subpressor dose of A61603, a highly selective and potent α1A agonist. Cardiac tissue and serum were analyzed using a non-targeted metabolomics approach. RESULTS: We identified previously unrecognized metabolic responses to α1A activation, most notably broad reduction in the abundance of polyunsaturated fatty acids (PUFAs) and endocannabinoids (ECs). CONCLUSION: Given the well characterized roles of PUFAs and ECs in inflammatory pathways, these findings suggest a possible role for cardiac α1A-ARs in the regulation of inflammation and may offer novel insight into the mechanisms underlying the cardioprotective benefit of selective pharmacologic α1A activation.
Authors: Mária Szekeres; György L Nádasy; Gábor Turu; Eszter Soltész-Katona; Zoltán Benyó; Stefan Offermanns; Éva Ruisanchez; Eszter Szabó; Zoltán Takáts; Sándor Bátkai; Zsuzsanna E Tóth; László Hunyady Journal: Mol Cell Endocrinol Date: 2015-01-13 Impact factor: 4.102
Authors: Rita Zrenner; Heike Riegler; Cathleen R Marquard; Peter R Lange; Claudia Geserick; Caren E Bartosz; Celine T Chen; Robert D Slocum Journal: New Phytol Date: 2009-04-29 Impact factor: 10.151