Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity.

Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity.

Doxorubicin is widely used as a first-line chemotherapeutic drug for various malignancies. However, doxorubicin causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to doxorubicin-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that doxorubicin induces the blockage of autophagic flux, which contributes to doxorubicin cardiotoxicity. This study investigated whether nicotinamide riboside, a precursor of NAD+, prevents doxorubicin cardiotoxicity by improving autophagic flux. We report that administration of nicotinamide riboside elevated NAD+ levels, and reduced cardiac injury and myocardial dysfunction in doxorubicin-injected mice. These protective effects of nicotinamide riboside were recapitulated in cultured cardiomyocytes upon doxorubicin treatment. Mechanistically, nicotinamide riboside prevented the blockage of autophagic flux, accumulation of autolysosomes and oxidative stress in doxorubicin-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of nicotinamide riboside during doxorubicin-induced cardiotoxicity. Collectively, our study shows that nicotinamide riboside enhances autolysosome clearance via the NAD+/SIRT1 signaling thereby preventing doxorubicin-triggered cardiotoxicity.

阿霉素被广泛用作多种恶性肿瘤的一线化疗药物。然而，阿霉素会导致严重的心脏毒性，这限制了它的临床应用。氧化应激是阿霉素诱导心脏毒性的主要因素之一。虽然自噬流是心肌细胞对抗氧化应激的一种重要防御机制，但近期研究表明，阿霉素会诱导自噬流受阻，这导致了阿霉素的心脏毒性。本研究探讨了烟酰胺核糖（一种NAD⁺的前体）是否通过改善自噬流来预防阿霉素的心脏毒性。我们报道，给予烟酰胺核糖提高了NAD⁺水平，并减轻了注射阿霉素的小鼠的心脏损伤和心肌功能障碍。在阿霉素处理的培养心肌细胞中也重现了烟酰胺核糖的这些保护作用。从机制上讲，烟酰胺核糖防止了阿霉素处理的心肌细胞中自噬流受阻、自溶酶体积累和氧化应激，这些作用与溶酶体酸化的恢复有关。此外，在阿霉素诱导的心脏毒性过程中，抑制溶酶体酸化或SIRT1会消除烟酰胺核糖的这些保护作用。总之，我们的研究表明，烟酰胺核糖通过NAD⁺/SIRT1信号通路增强自溶酶体清除，从而预防阿霉素引发的心脏毒性。