Effects of perhexiline-induced fuel switch on the cardiac proteome and metabolome

TY - JOUR

T1 - Effects of perhexiline-induced fuel switch on the cardiac proteome and metabolome

AU - Yin, Xiaoke

AU - Dwyer, Joseph

AU - Langley, Sarah R.

AU - Mayr, Ursula

AU - Xing, Qiuru

AU - Drozdov, Ignat

AU - Nabeebaccus, Adam

AU - Shah, Ajay M.

AU - Madhu, Basetti

AU - Griffiths, John

AU - Edwards, Lindsay M.

AU - Mayr, Manuel

PY - 2013/2/1

Y1 - 2013/2/1

N2 - Perhexiline is a potent anti-anginal drug used for treatment of refractory angina and other forms of heart disease. It provides an oxygen sparing effect in the myocardium by creating a switch from fatty acid to glucose metabolism through partial inhibition of carnitine palmitoyltransferase 1 and 2. However, the precise molecular mechanisms underlying the cardioprotective effects elicited by perhexiline are not fully understood. The present study employed a combined proteomics, metabolomics and computational approach to characterise changes in murine hearts upon treatment with perhexiline. According to results based on difference in-gel electrophoresis, the most profound change in the cardiac proteome related to the activation of the pyruvate dehydrogenase complex. Metabolomic analysis by high-resolution nuclear magnetic resonance spectroscopy showed lower levels of total creatine and taurine in hearts of perhexiline-treated mice. Creatine and taurine levels were also significantly correlated in a cross-correlation analysis of all metabolites. Computational modelling suggested that far from inducing a simple shift from fatty acid to glucose oxidation, perhexiline may cause complex rebalancing of carbon and nucleotide phosphate fluxes, fuelled by increased lactate and amino acid uptake, to increase metabolic flexibility and to maintain cardiac output. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".

AB - Perhexiline is a potent anti-anginal drug used for treatment of refractory angina and other forms of heart disease. It provides an oxygen sparing effect in the myocardium by creating a switch from fatty acid to glucose metabolism through partial inhibition of carnitine palmitoyltransferase 1 and 2. However, the precise molecular mechanisms underlying the cardioprotective effects elicited by perhexiline are not fully understood. The present study employed a combined proteomics, metabolomics and computational approach to characterise changes in murine hearts upon treatment with perhexiline. According to results based on difference in-gel electrophoresis, the most profound change in the cardiac proteome related to the activation of the pyruvate dehydrogenase complex. Metabolomic analysis by high-resolution nuclear magnetic resonance spectroscopy showed lower levels of total creatine and taurine in hearts of perhexiline-treated mice. Creatine and taurine levels were also significantly correlated in a cross-correlation analysis of all metabolites. Computational modelling suggested that far from inducing a simple shift from fatty acid to glucose oxidation, perhexiline may cause complex rebalancing of carbon and nucleotide phosphate fluxes, fuelled by increased lactate and amino acid uptake, to increase metabolic flexibility and to maintain cardiac output. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".

KW - Metabolomics

KW - Proteomics

KW - Cardioprotection

KW - Metabolism

KW - Heart failure

KW - PYRUVATE-DEHYDROGENASE

KW - FATTY-ACIDS

KW - RAT-HEART

KW - INHIBITION

KW - RESPONSES

KW - LIVER

U2 - 10.1016/j.yjmcc.2012.12.014

DO - 10.1016/j.yjmcc.2012.12.014

M3 - Article

C2 - 23277191

SN - 0022-2828

VL - 55

SP - 27

EP - 30

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

ER -