Coenzyme A (CoA) is an essential co-factor required for intermediary metabolism. Perturbations in homeostasis of CoA have been implicated in various pathologies; however, whether CoA homeostasis is changed and the extent to which CoA levels contribute to ventricular function and remodeling during pressure overload has not been explored. In this study, we sought to assess changes in CoA biosynthetic pathway during pressure overload and determine the impact of limiting CoA on cardiac function. We limited cardiac CoA levels by deleting the rate limiting enzyme in CoA biosynthesis, Pank1. We found that constitutive, cardiomyocyte-specific Pank1 deletion (cmPank1^-/-) significantly reduced PANK1 mRNA, PANK1 protein, and CoA levels compared to Pank1 sufficient littermates (cmPank1^+/+) but exerted no obvious deleterious impact on the mice at baseline. We then subjected both groups of mice to pressure overload-induced heart failure. Interestingly, there was more ventricular dilation in cmPank1^-/- during pressure overload. To explore potential mechanisms contributing to this phenotype, we performed transcriptomic profiling, which suggested a role for Pank1 in regulating fibrotic and metabolic processes during pressure overload. Indeed, Pank1 deletion exacerbated cardiac fibrosis following pressure overload. Because we were interested in the possibility of early metabolic impacts in response to pressure overload, we performed untargeted metabolomics, which indicated significant changes to metabolites involved in fatty acid and ketone metabolism, among other pathways. Collectively, our study underscores the role of elevated CoA levels in supporting fatty acid and ketone body oxidation, which may be more important than CoA-driven, enzyme-independent acetylation in the failing heart.

中文翻译：

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心脏 PANK1 缺失会加剧压力超负荷期间的心室功能障碍

辅酶 A (CoA) 是中间代谢所需的重要辅助因子。CoA 稳态的扰动与各种病理学有关。然而，尚未探讨 CoA 稳态是否发生变化以及 CoA 水平在压力超负荷期间对心室功能和重塑的贡献程度。在这项研究中，我们试图评估压力超负荷期间 CoA 生物合成途径的变化，并确定限制 CoA 对心脏功能的影响。我们通过删除 CoA 生物合成中的限速酶 Pank1 来限制心脏 CoA 水平。我们发现，与足够的 Pank1 同窝小鼠（cmPank1 ^+/+）相比，组成型心肌细胞特异性 Pank1 缺失 (cmPank1 ^-/-) 但对基线时的小鼠没有明显的有害影响。然后我们让两组小鼠承受压力超负荷引起的心力衰竭。有趣的是，在 cmPank1 中有更多的心室扩张^-/-在压力过载时。为了探索导致这种表型的潜在机制，我们进行了转录组分析，这表明 Pank1 在压力超负荷期间调节纤维化和代谢过程中的作用。事实上，Pank1 缺失加剧了压力超负荷后的心脏纤维化。因为我们对压力超负荷产生早期代谢影响的可能性感兴趣，所以我们进行了非靶向代谢组学，这表明脂肪酸和酮代谢等途径中涉及的代谢物发生了显着变化。总的来说，我们的研究强调了 CoA 水平升高在支持脂肪酸和酮体氧化方面的作用，这可能比衰竭心脏中 CoA 驱动的、酶非依赖性乙酰化更重要。