Modeling the transition from decompensated to pathological hypertrophy

Florencia Pascual, Jonathan C. Schisler, Trisha J. Grevengoed, Monte Willis, Rosalind A. Coleman

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background--Long-chain acyl-CoA synthetases (ACSL) catalyze the conversion of long-chain fatty acids to fatty acyl-CoAs. Cardiac-specific ACSL1 temporal knockout at 2 months results in a shift from FA oxidation toward glycolysis that promotes mTORC1-mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of fatty acid oxidation on cardiac metabolism, hypertrophy development, and function. Methods and Results--Global cardiac transcriptional analysis revealed differential expression of genes involved in cardiac metabolism, fibrosis, and hypertrophy development in Acsl1 H-/- hearts 2 weeks after Acsl1 ablation. Comparison of the 2- and 10-week transcriptional responses uncovered 137 genes whose expression was uniquely changed upon knockdown of cardiac ACSL1, including the distinct upregulation of fibrosis genes, a phenomenon not observed after complete ACSL1 knockout. Metabolomic analysis identified metabolites altered in hearts displaying partially reduced ACSL activity, and rapamycin treatment normalized the cardiac metabolomic fingerprint. Conclusions--Short-term cardiac-specific ACSL1 inactivation resulted in metabolic and transcriptional derangements distinct from those observed upon complete ACSL1 knockout, suggesting heart-specific mTOR (mechanistic target of rapamycin) signaling that occurs during the early stages of substrate switching. The hypertrophy observed with partial Acsl1 ablation occurs in the context of normal cardiac function and is reminiscent of a physiological process, making this a useful model to study the transition from physiological to pathological hypertrophy.

Original languageEnglish (US)
Article numbere008293
JournalJournal of the American Heart Association
Volume7
Issue number8
DOIs
StatePublished - Apr 17 2018
Externally publishedYes

Fingerprint

Hypertrophy
Metabolomics
Sirolimus
Gene Expression
Fibrosis
Fatty Acids
Coenzyme A Ligases
Physiological Phenomena
Acyl Coenzyme A
Cardiomegaly
Dermatoglyphics
Glycolysis
Up-Regulation
Genes

Keywords

  • Fatty acid
  • Fibrosis
  • Fuel switching
  • Glycolysis
  • Metabolomics
  • MTOR
  • Oxidation
  • RNAseq

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Modeling the transition from decompensated to pathological hypertrophy. / Pascual, Florencia; Schisler, Jonathan C.; Grevengoed, Trisha J.; Willis, Monte; Coleman, Rosalind A.

In: Journal of the American Heart Association, Vol. 7, No. 8, e008293, 17.04.2018.

Research output: Contribution to journalArticle

Pascual, Florencia ; Schisler, Jonathan C. ; Grevengoed, Trisha J. ; Willis, Monte ; Coleman, Rosalind A. / Modeling the transition from decompensated to pathological hypertrophy. In: Journal of the American Heart Association. 2018 ; Vol. 7, No. 8.
@article{66032c9f2b0c46aeb280a117550ea27f,
title = "Modeling the transition from decompensated to pathological hypertrophy",
abstract = "Background--Long-chain acyl-CoA synthetases (ACSL) catalyze the conversion of long-chain fatty acids to fatty acyl-CoAs. Cardiac-specific ACSL1 temporal knockout at 2 months results in a shift from FA oxidation toward glycolysis that promotes mTORC1-mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of fatty acid oxidation on cardiac metabolism, hypertrophy development, and function. Methods and Results--Global cardiac transcriptional analysis revealed differential expression of genes involved in cardiac metabolism, fibrosis, and hypertrophy development in Acsl1 H-/- hearts 2 weeks after Acsl1 ablation. Comparison of the 2- and 10-week transcriptional responses uncovered 137 genes whose expression was uniquely changed upon knockdown of cardiac ACSL1, including the distinct upregulation of fibrosis genes, a phenomenon not observed after complete ACSL1 knockout. Metabolomic analysis identified metabolites altered in hearts displaying partially reduced ACSL activity, and rapamycin treatment normalized the cardiac metabolomic fingerprint. Conclusions--Short-term cardiac-specific ACSL1 inactivation resulted in metabolic and transcriptional derangements distinct from those observed upon complete ACSL1 knockout, suggesting heart-specific mTOR (mechanistic target of rapamycin) signaling that occurs during the early stages of substrate switching. The hypertrophy observed with partial Acsl1 ablation occurs in the context of normal cardiac function and is reminiscent of a physiological process, making this a useful model to study the transition from physiological to pathological hypertrophy.",
keywords = "Fatty acid, Fibrosis, Fuel switching, Glycolysis, Metabolomics, MTOR, Oxidation, RNAseq",
author = "Florencia Pascual and Schisler, {Jonathan C.} and Grevengoed, {Trisha J.} and Monte Willis and Coleman, {Rosalind A.}",
year = "2018",
month = "4",
day = "17",
doi = "10.1161/JAHA.117.008293",
language = "English (US)",
volume = "7",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "8",

}

TY - JOUR

T1 - Modeling the transition from decompensated to pathological hypertrophy

AU - Pascual, Florencia

AU - Schisler, Jonathan C.

AU - Grevengoed, Trisha J.

AU - Willis, Monte

AU - Coleman, Rosalind A.

PY - 2018/4/17

Y1 - 2018/4/17

N2 - Background--Long-chain acyl-CoA synthetases (ACSL) catalyze the conversion of long-chain fatty acids to fatty acyl-CoAs. Cardiac-specific ACSL1 temporal knockout at 2 months results in a shift from FA oxidation toward glycolysis that promotes mTORC1-mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of fatty acid oxidation on cardiac metabolism, hypertrophy development, and function. Methods and Results--Global cardiac transcriptional analysis revealed differential expression of genes involved in cardiac metabolism, fibrosis, and hypertrophy development in Acsl1 H-/- hearts 2 weeks after Acsl1 ablation. Comparison of the 2- and 10-week transcriptional responses uncovered 137 genes whose expression was uniquely changed upon knockdown of cardiac ACSL1, including the distinct upregulation of fibrosis genes, a phenomenon not observed after complete ACSL1 knockout. Metabolomic analysis identified metabolites altered in hearts displaying partially reduced ACSL activity, and rapamycin treatment normalized the cardiac metabolomic fingerprint. Conclusions--Short-term cardiac-specific ACSL1 inactivation resulted in metabolic and transcriptional derangements distinct from those observed upon complete ACSL1 knockout, suggesting heart-specific mTOR (mechanistic target of rapamycin) signaling that occurs during the early stages of substrate switching. The hypertrophy observed with partial Acsl1 ablation occurs in the context of normal cardiac function and is reminiscent of a physiological process, making this a useful model to study the transition from physiological to pathological hypertrophy.

AB - Background--Long-chain acyl-CoA synthetases (ACSL) catalyze the conversion of long-chain fatty acids to fatty acyl-CoAs. Cardiac-specific ACSL1 temporal knockout at 2 months results in a shift from FA oxidation toward glycolysis that promotes mTORC1-mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of fatty acid oxidation on cardiac metabolism, hypertrophy development, and function. Methods and Results--Global cardiac transcriptional analysis revealed differential expression of genes involved in cardiac metabolism, fibrosis, and hypertrophy development in Acsl1 H-/- hearts 2 weeks after Acsl1 ablation. Comparison of the 2- and 10-week transcriptional responses uncovered 137 genes whose expression was uniquely changed upon knockdown of cardiac ACSL1, including the distinct upregulation of fibrosis genes, a phenomenon not observed after complete ACSL1 knockout. Metabolomic analysis identified metabolites altered in hearts displaying partially reduced ACSL activity, and rapamycin treatment normalized the cardiac metabolomic fingerprint. Conclusions--Short-term cardiac-specific ACSL1 inactivation resulted in metabolic and transcriptional derangements distinct from those observed upon complete ACSL1 knockout, suggesting heart-specific mTOR (mechanistic target of rapamycin) signaling that occurs during the early stages of substrate switching. The hypertrophy observed with partial Acsl1 ablation occurs in the context of normal cardiac function and is reminiscent of a physiological process, making this a useful model to study the transition from physiological to pathological hypertrophy.

KW - Fatty acid

KW - Fibrosis

KW - Fuel switching

KW - Glycolysis

KW - Metabolomics

KW - MTOR

KW - Oxidation

KW - RNAseq

UR - http://www.scopus.com/inward/record.url?scp=85045304788&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85045304788&partnerID=8YFLogxK

U2 - 10.1161/JAHA.117.008293

DO - 10.1161/JAHA.117.008293

M3 - Article

C2 - 29622588

AN - SCOPUS:85045304788

VL - 7

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 8

M1 - e008293

ER -