NAD+ repletion restores cardioprotective autophagy and mitophagy in obesity-associated heart failure by suppressing excessive trophic signaling.

Mahmoud Abdellatif, Francisco Vasques-Nóvoa, João Pedro Ferreira, Junichi Sadoshima, Abhinav Diwan, Wolfgang A Linke, Guido Kroemer, Simon Sedej
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Abstract

Macroautophagy/autophagy is markedly inhibited in the hearts of elderly obese patients with heart failure and preserved ejection fraction (HFpEF). However, the therapeutic relevance and underlying signaling mechanisms of the decline of autophagy in HFpEF remain unclear. We observed that therapeutic nicotinamide adenine dinucleotide (NAD+) repletion via nicotinamide supplementation restores cardioprotective autophagy and mitophagy in preclinical models of obesity-related HFpEF. Targeted and untargeted cardiac acetylome profiling revealed no significant deacetylation of essential autophagy-related proteins, including ATG5, ATG7 and mammalian Atg8-family members (ATG8s), suggesting a SIRT (sirtuin)-independent mechanism of autophagy induction by nicotinamide. Instead, cardiac transcriptomic analysis revealed major shifts in insulin-IGF1 (insulin-like growth factor 1) signaling, a known autophagy inhibitory pathway. Nicotinamide supplementation reversed the HFpEF-associated increase in insulin-IGF1 signaling, whereas exogenous IGF1 counteracts nicotinamide-induced autophagy. Importantly, nicotinamide fails to exert cardioprotective effects in mice lacking the autophagy-related protein ATG5 in cardiomyocytes, implicating autophagy as essential for the therapeutic response. In patients with HFpEF, a metabolic shift diverting nicotinamide away from NAD+ biosynthesis toward catabolism strongly correlates with worsening heart failure and increased cardiovascular mortality, even after adjusting for traditional risk factors. In sum, we demonstrate that NAD+ replenishment improves cardiometabolic HFpEF by restoring cardiac autophagy through suppression of excessive IGF1 signaling.

NAD+充盈通过抑制过度营养信号恢复肥胖相关心力衰竭的心脏保护性自噬和线粒体自噬。
老年肥胖合并心力衰竭和保留射血分数(HFpEF)患者的心脏巨噬/自噬明显受到抑制。然而,HFpEF中自噬下降的治疗相关性和潜在的信号机制仍不清楚。我们观察到,在肥胖相关HFpEF的临床前模型中,通过补充烟酰胺来补充治疗性烟酰胺腺嘌呤二核苷酸(NAD+)可恢复心脏保护性自噬和线粒体自噬。靶向和非靶向心脏乙酰组分析显示,包括ATG5、ATG7和哺乳动物atg8家族成员(ATG8s)在内的重要自噬相关蛋白没有明显的去乙酰化,这表明烟酰胺诱导自噬的机制不依赖于SIRT (sirtuin)。相反,心脏转录组学分析揭示了胰岛素- igf1(胰岛素样生长因子1)信号传导的主要变化,这是一种已知的自噬抑制途径。烟酰胺的补充逆转了hfpef相关的胰岛素-IGF1信号的增加,而外源的IGF1抵消了烟酰胺诱导的自噬。重要的是,在心肌细胞中缺乏自噬相关蛋白ATG5的小鼠中,烟酰胺未能发挥心脏保护作用,这意味着自噬对治疗反应至关重要。在HFpEF患者中,即使在调整了传统危险因素后,将烟酰胺从NAD+生物合成转向分解代谢的代谢转变与心力衰竭恶化和心血管死亡率增加密切相关。总之,我们证明NAD+的补充通过抑制过量的IGF1信号传导来恢复心脏自噬,从而改善心脏代谢的HFpEF。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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