Modeling the Transition From Decompensated to Pathological Hypertrophy

Abstract

BackgroundLong‐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 ResultsGlobal 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.ConclusionsShort‐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.

Cardiomyocyte-specific ACSL1 Deficiency Prevents Cardiac Lipotoxicity and Alleviates Heart Dysfunction in the ob/ob Model of Obesity

“…Although both total and short-term Acsl1 inactivation result in increased LV mass [17,18], partial Acsl1 abrogation did not exacerbate the hypertrophy observed in obese hearts. Obese hearts exhibited only mild cardiac fibrosis, in agreement with the discordant findings of other studies [32,33], and partial ACSL1 deficiency was associated with a moderate and transient upregulation in fibrosis [19] in both lean and obese mice that disappeared 5 weeks after knockout induction. Finally, partial Acsl1 ablation drastically reduced ventricular TAG content, ameliorated cardiac dysfunction, and was protective in ob/ob hearts subjected to stress.…”

“…Moreover, ob/ob hearts exhibited hallmarks of dilated cardiomyopathy and reduced contractility including increased LV diameter, LV volume, and stroke volume, all of which resolved 5 weeks after Acsl1 knockdown ( Table 2). We posit that the temporary dip in function resulted from an initial compensatory process during which cardiac efficiency is decreased through oxygen use for non-contractile purposes [19,28], and that it had not been previously observed due to differences in age and gender of the animals studied [17,18,29]. deficiency likely protects obese hearts that are subjected to stress.…”

“…Conversely, partial deficiency of ACSL1-mediated FA activation observed 2 weeks after tamoxifen treatment induces changes in cardiac metabolism and size without affecting heart function [19].…”

“…However, long-term ACSL1 inactivation is also accompanied by deleterious effects, including glucose intolerance, development of mTORC1-mediated pathological hypertrophy, and diastolic dysfunction [17,18]. In contrast, partial (~60%) cardiac ACSL1 knockdown is sufficient to elicit cardiac-specific metabolic derangements and the development of hypertrophy without affecting cardiac function [19]. We therefore hypothesized that partial Acsl1 ablation could reverse ventricular TAG accumulation and ameliorate myocardial dysfunction in the ob/ob model of cardiomyopathy.…”

Fenofibrate Induced Cardiac Fibrosis in Mice Deficient in the Protein Quality Control Regulator, CHIP

“…Pressure overload and the subsequent pathological remodeling in the heart is associated with changes in cardiac metabolism [41][42][43]. In the initial compensatory phase of pressure overload, the heart adapts to the increased demand and can maintain cardiac output; however, over time, if the stress is not relieved, this adaptation turns to maladaptation and eventual heart failure.…”