PGC-1β Deficiency Accelerates the Transition to Heart Failure in Pressure Overload Hypertrophy

Christian Riehle; Adam R Wende; Vlad G Zaha; Karla Maria Pires; Benjamin Wayment; Curtis Olsen; Heiko Bugger; Jonathan Buchanan; Xiaohui Wang; Annie Bello Moreira; Torsten Doenst; Gema Medina-Gomez; Sheldon E Litwin; Christopher J Lelliott; Antonio Vidal-Puig; E. Dale Abel

doi:10.1161/CIRCRESAHA.111.243964

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PGC-1β Deficiency Accelerates the Transition to Heart Failure in Pressure Overload Hypertrophy

Journal article

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PGC-1β Deficiency Accelerates the Transition to Heart Failure in Pressure Overload Hypertrophy

Christian Riehle, Adam R Wende, Vlad G Zaha, Karla Maria Pires, Benjamin Wayment, Curtis Olsen, Heiko Bugger, Jonathan Buchanan, Xiaohui Wang, Annie Bello Moreira, …

Circulation research, Vol.109(7), pp.783-793

09/16/2011

DOI: 10.1161/CIRCRESAHA.111.243964

PMID: 21799152

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Abstract

Rationale: Pressure overload cardiac hypertrophy, a risk factor for heart failure, is associated with reduced mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) proteins that correlate in rodents with reduced PGC-1α expression. Objective: To determine the role of PGC-1β in maintaining mitochondrial energy metabolism and contractile function in pressure overload hypertrophy. Methods and results: PGC-1β deficient (KO) mice and wildtype (WT) controls were subjected to transverse aortic constriction (TAC). Although LV function was modestly reduced in young KO hearts, there was no further decline with age so that LV function was similar between KO and WT when TAC was performed. WT-TAC mice developed relatively compensated LVH, despite reduced mitochondrial function and repression of OXPHOS and FAO genes. In nonstressed KO hearts, OXPHOS gene expression and palmitoyl-carnitine-supported mitochondrial function were reduced to the same extent as banded WT, but FAO gene expression was normal. Following TAC, KO mice progressed more rapidly to heart failure and developed more severe mitochondrial dysfunction, despite a similar overall pattern of repression of OXPHOS and FAO genes as WT-TAC. However, in relation to WT-TAC, PGC-1β deficient mice exhibited greater degrees of oxidative stress, decreased cardiac efficiency, lower rates of glucose metabolism, and repression of hexokinase II protein. Conclusions: PGC-1β plays an important role in maintaining baseline mitochondrial function and cardiac contractile function following pressure overload hypertrophy by preserving glucose metabolism and preventing oxidative stress.

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Title: Subtitle: PGC-1β Deficiency Accelerates the Transition to Heart Failure in Pressure Overload Hypertrophy
Creators: Christian Riehle - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Adam R Wende - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Vlad G Zaha - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Karla Maria Pires - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Benjamin Wayment - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Curtis Olsen - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Heiko Bugger - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Jonathan Buchanan - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Xiaohui Wang - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Annie Bello Moreira - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Torsten Doenst - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Gema Medina-Gomez - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Sheldon E Litwin - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Christopher J Lelliott - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Antonio Vidal-Puig - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
E. Dale Abel - From the Division of Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, Utah (C.R., A.R.W., V.G.C., K.M.P., C.O., H.B., J.B., A.B.M., E.D.A.); Division of Cardiology, University of Utah, Salt Lake City, Utah (B.W., X.W., S.E.L.); Department of Biosciences, AstraZeneca R&D, Mölndal S-43183, Sweden (C.J.L.); University of Cambridge. Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital
Resource Type: Journal article
Publication Details: Circulation research, Vol.109(7), pp.783-793
DOI: 10.1161/CIRCRESAHA.111.243964
PMID: 21799152
ISSN: 0009-7330
eISSN: 1524-4571
Language: English
Date published: 09/16/2011
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024401302771

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