Tài liệu Báo cáo khoa học: Metabolic gene switching in the murine female heart parallels enhanced

Metabolic gene switching in the murine female heart

parallels enhanced mitochondrial respiratory function in

response to oxidative stress

M. Faadiel Essop1,2, W. Y. A. Chan2 and Heinrich Taegtmeyer3

1 Department of Physiological Sciences, Stellenbosch University, South Africa

2 Hatter Heart Research Institute, Faculty of Health Sciences, University of Cape Town, South Africa

3 Department of Internal Medicine, Division of Cardiology, University of Texas, Houston Medical School, TX, USA

Premenopausal women have a lower risk for develop￾ing cardiovascular disease as compared to age-matched

males [1]. Moreover, experimental studies show increa￾sed resistance to ischemia ⁄reperfusion injury in female

versus male hearts [2,3]. The molecular regulatory

mechanisms underlying such gender-based differences

are unclear. However, estrogen may play a key role in

this process [4], and is thought to signal its cardio￾protective effects via the prosurvival serine-threonine

protein kinase, Akt (also known as protein kinase B)

[2]. In agreement with this, elevated levels of activated

Akt in female hearts are linked to improved cardiac

cell survival [5], and a recent study implicated the

PI3-K ⁄Akt signaling pathway in estrogen-mediated

cardioprotection [6].

Adaptive metabolic remodeling is considered to be

an important component of cardioprotective mecha￾nisms in response to decreased oxygen supply. For

example, enhanced glucose utilization is proposed to

confer cardioprotective effects in response to ische￾mia ⁄reperfusion [7]. Conversely, higher rates of fatty

acid oxidation during ischemia may uncouple mito￾chondrial oxidative phosphorylation and ⁄ or increase

proton production, contributing to impaired contractile

Keywords

bioenergetics; cardiovascular disease;

gender differences; gene expression;

mitochondrial respiration

Correspondence

M. F. Essop, Department of Physiological

Sciences, Stellenbosch University,

Room 2009, Mike De Vries Building,

Merriman Avenue, Stellenbosch 7600,

South Africa

Fax: +27 21 808 3145

Tel: +27 21 808 4507

E-mail: [email protected]

(Received 14 December 2006, revised

14 August 2007, accepted 17 August 2007)

doi:10.1111/j.1742-4658.2007.06051.x

The mechanisms underlying increased cardioprotection in younger female

mice are unclear. We hypothesized that serine-threonine protein kinase

(protein kinase B; Akt) triggers a metabolic gene switch (decreased fatty

acids, increased glucose) in female hearts to enhance mitochondrial bio￾energetic capacity, conferring protection against oxidative stress. Here, we

employed male and female control (db ⁄+) and obese (db ⁄ db) mice. We

found diminished transcript levels of peroxisome proliferator-activated

receptor-alpha, muscle-type carnitine palmitoyltransferase 1 and pyruvate

dehydrogenase kinase 4 in female control hearts versus male hearts. More￾over, females displayed improved recovery of cardiac mitochondrial respi￾ratory function and higher ATP levels versus males in response to acute

oxygen deprivation. All these changes were reversed in female db ⁄ db

hearts. However, we found no significant gender-based differences in levels

of Akt, suggesting that Akt-independent signaling mechanisms are respon￾sible for the resilient mitochondrial phenotype observed in female mouse

hearts. As glucose is a more energetically efficient fuel substrate when oxy￾gen is limiting, this gene program may be a crucial component that

enhances tolerance to oxygen deprivation in female hearts.

Abbreviations

Akt, serine-threonine protein kinase (protein kinase B); GLUT, glucose transporter; MCAD, medium-chain acyl-CoA dehydrogenase; mCPT1,

muscle-type carnitine palmitoyltransferase 1; PDK-4, pyruvate dehydrogenase kinase 4; PGC-1, peroxisome proliferator-activated receptor￾gamma coactivator-1; PPARa, peroxisome proliferator-activated receptor-alpha; UCP3, uncoupling protein 3.

5278 FEBS Journal 274 (2007) 5278–5284 ª 2007 The Authors Journal compilation ª 2007 FEBS