Deficiency of cardiac Acyl-CoA synthetase-1 induces diastolic dysfunction, but pathologic hypertrophy is reversed by rapamycin

David S. Paul, Trisha J. Grevengoed, Florencia Pascual, Jessica M. Ellis, Monte Willis, Rosalind A. Coleman

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

In mice with temporally-induced cardiac-specific deficiency of acyl-CoA synthetase-1 (Acsl1H -/-), the heart is unable to oxidize long-chain fatty acids and relies primarily on glucose for energy. These metabolic changes result in the development of both a spontaneous cardiac hypertrophy and increased phosphorylated S6 kinase (S6K), a substrate of the mechanistic target of rapamycin, mTOR. Doppler echocardiography revealed evidence of significant diastolic dysfunction, indicated by a reduced E/A ratio and increased mean performance index, although the deceleration time and the expression of sarco/endoplasmic reticulum calcium ATPase and phospholamban showed no difference between genotypes. To determine the role of mTOR in the development of cardiac hypertrophy, we treated Acsl1H -/- mice with rapamycin. Six to eight week old Acsl1H -/- mice and their littermate controls were given i.p. tamoxifen to eliminate cardiac Acsl1, then concomitantly treated for 10 weeks with i.p. rapamycin or vehicle alone. Rapamycin completely blocked the enhanced ventricular S6K phosphorylation and cardiac hypertrophy and attenuated the expression of hypertrophy-associated fetal genes, including α-skeletal actin and B-type natriuretic peptide. mTOR activation of the related Acsl3 gene, usually associated with pathologic hypertrophy, was also attenuated in the Acsl1H -/- hearts, indicating that alternative pathways of fatty acid activation did not compensate for the loss of Acsl1. Compared to controls, Acsl1H -/- hearts exhibited an 8-fold higher uptake of 2-deoxy[1-14C]glucose and a 35% lower uptake of the fatty acid analog 2-bromo[1-14C]palmitate. These data indicate that Acsl1-deficiency causes diastolic dysfunction and that mTOR activation is linked to the development of cardiac hypertrophy in Acsl1H -/- mice.

Original languageEnglish (US)
Pages (from-to)880-887
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1841
Issue number6
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Coenzyme A Ligases
Cardiomegaly
Sirolimus
Hypertrophy
Ribosomal Protein S6 Kinases
Fatty Acids
Glucose
Deceleration
Calcium-Transporting ATPases
Doppler Echocardiography
Palmitates
Brain Natriuretic Peptide
Tamoxifen
Endoplasmic Reticulum
Genes
Actins
Genotype
Phosphorylation

Keywords

  • Fatty acid oxidation
  • Gene expression
  • Insulin resistance
  • mTOR
  • Substrate switching
  • Ventricular function

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Deficiency of cardiac Acyl-CoA synthetase-1 induces diastolic dysfunction, but pathologic hypertrophy is reversed by rapamycin. / Paul, David S.; Grevengoed, Trisha J.; Pascual, Florencia; Ellis, Jessica M.; Willis, Monte; Coleman, Rosalind A.

In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, Vol. 1841, No. 6, 01.01.2014, p. 880-887.

Research output: Contribution to journalArticle

Paul, David S. ; Grevengoed, Trisha J. ; Pascual, Florencia ; Ellis, Jessica M. ; Willis, Monte ; Coleman, Rosalind A. / Deficiency of cardiac Acyl-CoA synthetase-1 induces diastolic dysfunction, but pathologic hypertrophy is reversed by rapamycin. In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. 2014 ; Vol. 1841, No. 6. pp. 880-887.
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