Changes in the cardiac metabolome caused by perhexiline treatment in a mouse model of hypertrophic cardiomyopathy

被引：38

作者：

Gehmlich, Katja ^{[1
]}

Dodd, Michael S. ^{[2
]}

Allwood, J. William ^{[3
]}

Kelly, Matthew ^{[1
]}

Bellahcene, Mohamed ^{[1
]}

Lad, Heena V. ^{[1
]}

Stockenhuber, Alexander ^{[1
]}

Hooper, Charlotte ^{[1
]}

Ashrafian, Houman ^{[1
]}

Redwood, Charles S. ^{[1
]}

Carrier, Lucie ^{[4
,5
]}

Dunn, Warwick B. ^{[3
]}

机构：

[1] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford OX3 9DU, England

[2] Univ Oxford, Cardiac Metab Res Grp, Dept Physiol Anat & Genet, Oxford OX3 9DU, England

[3] Univ Birmingham, Sch Biosci, Birmingham, W Midlands, England

[4] Univ Med Ctr, Cardiovasc Res Ctr, Dept Expt Pharmacol & Toxicol, Hamburg, Germany

[5] DZHK German Ctr Cardiovasc Res, Berlin, Germany

来源：

MOLECULAR BIOSYSTEMS | 2015年 / 11卷 / 02期

基金：

英国惠康基金;

关键词：

KNOCK-IN MICE; OXIDATIVE STRESS; ANGINA-PECTORIS; SUDDEN-DEATH; LARGE-SCALE; PREVENTION; DYSFUNCTION; GUIDELINES; MANAGEMENT; MUTATIONS;

D O I：

10.1039/c4mb00594e

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Energy depletion has been highlighted as an important contributor to the pathology of hypertrophic cardiomyopathy (HCM), a common inherited cardiac disease. Pharmacological reversal of energy depletion appears an attractive approach and the use of perhexiline has been proposed as it is thought to shift myocardial metabolism from fatty acid to glucose utilisation, increasing ATP production and myocardial efficiency. We used the Mybpc3-targeted knock-in mouse model of HCM to investigate changes in the cardiac metabolome following perhexiline treatment. Echocardiography indicated that perhexiline induced partial improvement of some, but not all hypertrophic parameters after six weeks. Non-targeted metabolomics, applying ultra-high performance liquid chromatography-mass spectrometry, described a phenotypic modification of the cardiac metabolome with 272 unique metabolites showing a statistically significant change (p < 0.05). Changes in fatty acids and acyl carnitines indicate altered fatty acid transport into mitochondria, implying reduction in fatty acid beta-oxidation. Increased glucose utilisation is indirectly implied through changes in the glycolytic, glycerol, pentose phosphate, tricarboxylic acid and pantothenate pathways. Depleted reduced glutathione and increased production of NADPH suggest reduction in oxidative stress. These data delineate the metabolic changes occurring during improvement of the HCM phenotype and indicate the requirements for further targeted interventions.

引用

页码：564 / 573

页数：10

共 36 条

[1] Metabolic Modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy [J].

Abozguia, Khalid ;

Elliott, Perry ;

McKenna, William ;

Phan, Thanh Trung ;

Nallur-Shivu, Ganesh ;

Ahmed, Ibrar ;

Maher, Abdul R. ;

Kaur, Kulvinder ;

Taylor, Jenny ;

Henning, Anke ;

Ashrafian, Houman ;

Watkins, Hugh ;

Frenneaux, Michael .

CIRCULATION, 2010, 122 (16) :1562-U56

[2] Hypertrophic cardiomyopathy: a paradigm for myocardial energy depletion [J].

Ashrafian, H ;

Redwood, C ;

Blair, E ;

Watkins, H .

TRENDS IN GENETICS, 2003, 19 (05) :263-268

[3] Perhexiline [J].

Ashrafian, Houman ;

Horowitz, John D. ;

Frenneaux, Michael P. .

CARDIOVASCULAR DRUG REVIEWS, 2007, 25 (01) :76-97

[4] Mass spectrometry tools and metabolite-specific databases for molecular identification in metabolomics [J].

Brown, M. ;

Dunn, W. B. ;

Dobson, P. ;

Patel, Y. ;

Winder, C. L. ;

Francis-McIntyre, S. ;

Begley, P. ;

Carroll, K. ;

Broadhurst, D. ;

Tseng, A. ;

Swainston, N. ;

Spasic, I. ;

Goodacre, R. ;

Kell, D. B. .

ANALYST, 2009, 134 (07) :1322-1332

[5] Automated workflows for accurate mass-based putative metabolite identification in LC/MS-derived metabolomic datasets [J].

Brown, Marie ;

Wedge, David C. ;

Goodacre, Royston ;

Kell, Douglas B. ;

Baker, Philip N. ;

Kenny, Louise C. ;

Mamas, Mamas A. ;

Neyses, Ludwig ;

Dunn, Warwick B. .

BIOINFORMATICS, 2011, 27 (08) :1108-1112

[6] Recent advances in understanding serotonin regulation of cardiovascular function [J].

Côté, F ;

Fligny, C ;

Fromes, Y ;

Mallet, J ;

Vodjdani, G .

TRENDS IN MOLECULAR MEDICINE, 2004, 10 (05) :232-238

[7] Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy [J].

Crilley, JG ;

Boehm, EA ;

Blair, E ;

Rajagopalan, B ;

Blamire, AM ;

Styles, P ;

McKenna, WJ ;

Östman-Smith, I ;

Clarke, K ;

Watkins, H .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2003, 41 (10) :1776-1782

[8] Enhanced oxidative stress in hypertrophic cardiomyopathy [J].

Dimitrow, Pawel R. ;

Undas, Anetta ;

Wolkow, Pawel ;

Tracz, Wieslawa ;

Dubiel, Jacek S. .

PHARMACOLOGICAL REPORTS, 2009, 61 (03) :491-495

[9]

Dunn WB, 2012, BIOANALYSIS, V4, P2249, DOI [10.4155/BIO.12.204, 10.4155/bio.12.204]

[10] Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry [J].

Dunn, Warwick B. ;

Broadhurst, David ;

Begley, Paul ;

Zelena, Eva ;

Francis-McIntyre, Sue ;

Anderson, Nadine ;

Brown, Marie ;

Knowles, Joshau D. ;

Halsall, Antony ;

Haselden, John N. ;

Nicholls, Andrew W. ;

Wilson, Ian D. ;

Kell, Douglas B. ;

Goodacre, Royston .

NATURE PROTOCOLS, 2011, 6 (07) :1060-1083

← 1 2 3 4 →