期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 158, 期 -, 页码 1-10出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2021.05.004
关键词
Heart failure; Energy metabolism; Fatty acid oxidation
资金
- German Research Foundation (DFG) [RI 2764/1-1]
- Mitochondria and Metabolism Center Seed Grant
- U.S. National Institutes of Health (NIH) [HL-129510, HL-142628]
- American Heart Association Scientist Development Grant [14SDG18590020]
- American Heart Association [20PRE35120126]
- Biomedical Research Support Shared Instrumentation Grant [S10RR029021]
The study revealed a sex-dependent regulation of PPAR alpha signaling pathway in heart failure, which accounted for the differential response to ACC2 deletion. Male mice showed downregulation in mitochondrial oxidative function under pressure overload, and the improvement in cardiac function with ACC2 deletion was limited. In contrast, mitochondrial oxidative capacity was sustained in female mice under pressure overload, and ACC2 deletion improved myocardial energetics.
Background: Reduced fatty acid oxidation (FAO) is a hallmark of metabolic remodeling in heart failure. Enhancing mitochondrial long-chain fatty acid uptake by Acetyl-CoA carboxylase 2 (ACC2) deletion increases FAO and prevents cardiac dysfunction during chronic stresses, but therapeutic efficacy of this approach has not been determined. Methods: Male and female ACC2 f/f-MCM (ACC2KO) and their respective littermate controls were subjected to chronic pressure overload by TAC surgery. Tamoxifen injection 3 weeks after TAC induced ACC2 deletion and increased FAO in ACC2KO mice with pathological hypertrophy. Results: ACC2 deletion in mice with pre-existing cardiac pathology promoted FAO in female and male hearts, but improved cardiac function only in female mice. In males, pressure overload caused a downregulation in the mitochondrial oxidative function. Stimulating FAO by ACC2 deletion caused unproductive acyl-carnitine accumulation, which failed to improve cardiac energetics. In contrast, mitochondrial oxidative capacity was sustained in female pressure overloaded hearts and ACC2 deletion improved myocardial energetics. Mechanistically, we revealed a sex-dependent regulation of PPAR alpha signaling pathway in heart failure, which accounted for the differential response to ACC2 deletion. Conclusion: Metabolic remodeling in the failing heart is sex-dependent which could determine the response to metabolic intervention. The findings suggest that both mitochondrial oxidative capacity and substrate preference should be considered for metabolic therapy of heart failure.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据