Background. Cardiac hypertrophy is a compensatory response to pressure overload, which eventually leads to heart failure. The current study explored the protective effect of nicotinamide riboside (NR), a NAD⁺ booster that may be administered through the diet, on the occurrence of myocardial hypertrophy and revealed details of its underlying mechanism. Methods. Transverse aortic constriction (TAC) surgery was performed to establish a murine model of myocardial hypertrophy. Mice were randomly divided into four groups: sham, TAC, sham+NR, and TAC+NR. NR treatment was given daily by oral gavage. Cardiac structure and function were assessed using small animal echocardiography. Mitochondrial oxidative stress was evaluated by dihydroethidium (DHE) staining, malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity. Levels of expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), IL-1β, TNF-α, and Sirtuin3 were measured by real-time PCR and ELISA. Expression levels of Caspase-1, Caspase-1 pro, cleaved Gasdermin D (GSDMD), NLRP3, ASC, Sirtuin3, ac-MnSOD, and total MnSOD were measured by Western blot. Results. Reductions in the heart/body mass ratio (HW/BW) and lung/body mass ratio (LW/BW) and in ANP, BNP, and LDH levels were observed in the TAC group on the administration of NR (). Moreover, echocardiography data showed that cardiac dysfunction and structural changes caused by TAC were improved by NR treatment (). NR treatment also reduced levels of the inflammatory cytokines, IL-1β and TNF-α, and attenuated activation of NLRP3 inflammasomes induced by TAC. Furthermore, changes in DHE staining, MDA content, and SOD activity indicated that NR treatment alleviated the oxidative stress caused by TAC. Data from ELISA and Western blots revealed elevated myocardial NAD⁺ content and Sirtuin3 activity and decreased acetylation of MnSOD after NR treatment, exposing aspects of the underlying signaling pathway. Conclusion. NR treatment alleviated TAC-induced pathological cardiac hypertrophy and dysfunction. Mechanically, these beneficial effects were attributed to the inhibition of NLRP3 inflammasome activation and myocardial inflammatory response by regulating the NAD⁺-Sirtuin3-MnSOD signaling pathway.

中文翻译：

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烟酰胺核苷可减轻压力超负荷心脏肥大中的心脏功能障碍和重塑

背景。心脏肥大是对压力超负荷的一种代偿反应，最终导致心力衰竭。目前的研究探讨了烟酰胺核苷 (NR) 对心肌肥大发生的保护作用，^并揭示了其潜在机制的细节。方法. 进行横向主动脉缩窄（TAC）手术以建立小鼠心肌肥大模型。将小鼠随机分为四组：假手术组、TAC组、假手术组+NR组和TAC+NR组。每天通过口服强饲法给予NR治疗。使用小动物超声心动图评估心脏结构和功能。通过二氢乙锭 (DHE) 染色、丙二醛 (MDA) 含量和超氧化物歧化酶 (SOD) 活性评估线粒体氧化应激。通过实时荧光定量 PCR 和 ELISA 检测心房利钠肽 (ANP)、脑利钠肽 (BNP)、IL-1 β、TNF - α和 Sirtuin3 的表达水平。通过蛋白质印迹测量 Caspase-1、Caspase-1 pro、cleaved Gasdermin D (GSDMD)、NLRP3、ASC、Sirtuin3、ac-MnSOD 和总 MnSOD 的表达水平。结果。在给予 NR 后，在 TAC 组中观察到心脏/身体质量比 (HW/BW) 和肺/身体质量比 (LW/BW) 以及 ANP、BNP 和 LDH 水平的降低。）。此外，超声心动图数据显示，由 TAC 引起的心功能不全和结构改变通过 NR 治疗得到改善。）。NR 治疗还降低了炎症细胞因子 IL-1 β和 TNF - α的水平，并减弱了 TAC 诱导的 NLRP3 炎症小体的活化。此外，DHE 染色、MDA 含量和 SOD 活性的变化表明 NR 处理减轻了 TAC 引起的氧化应激。来自 ELISA 和蛋白质印迹的数据显示，NR 处理后心肌 NAD ⁺含量和 Sirtuin3 活性升高，MnSOD 乙酰化降低，暴露了潜在信号通路的各个方面。结论. NR 治疗减轻了 TAC 诱导的病理性心脏肥大和功能障碍。机械地，这些有益作用归因于通过调节 NAD ⁺ -Sirtuin3-MnSOD 信号通路抑制 NLRP3 炎性体活化和心肌炎症反应。