Modeling the Transition From Decompensated to Pathological Hypertrophy

作者：Pascual Florencia; Schisler Jonathan C; Grevengoed Trisha J; Willis Monte S; Coleman Rosalind A^*

来源：Journal of the American Heart Association, 2018, 7(8): e008293.

DOI：10.1161/JAHA.117.008293

• fatty acid
• fibrosis
• fuel switching
• glycolysis
• metabolomics
• mTOR
• oxidation
• RNAseq

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.

• 出版日期2018-4-17