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

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)783-793
Number of pages11
JournalCirculation research
Volume109
Issue number7
DOIs
StatePublished - Sep 16 2011

Keywords

  • cardiac hypertrophy
  • gene expression
  • heart failure
  • mitochondria

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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