武汉大学Qi-zhu Tang等研究人员合作发现，Macrod1通过调节PARP1-NAD⁺-SIRT3通路抑制糖尿病心肌病。相关论文于2024年3月8日在线发表在《中国药理学报》杂志上。

研究人员表示，糖尿病心肌病（DCM）是糖尿病最严重的长期后果之一，与心脏的氧化应激、炎症和细胞凋亡密切相关。含MACRO结构域1（Macrod1）是一种ADP-核糖水解酶1，高度富集于线粒体，参与心血管疾病的发病机制。

研究人员探讨了Macrod1在DCM中的作用。研究人员通过喂食高脂饮食（HFD）和腹腔注射链脲佐菌素（STZ）建立了小鼠模型。研究人员发现，Macrod1在DCM小鼠心脏组织中的表达水平明显下调。在体外用棕榈酸（PA，400μM）处理的新生大鼠心肌细胞（NRCM）中也观察到了Macrod1表达的降低。在DCM小鼠中敲除Macrod1不仅会恶化血糖控制，还会加重心脏重塑、线粒体功能障碍、NAD⁺消耗和氧化应激，而心脏特异性过表达Macrod1则可部分逆转这些病理过程。在经PA处理的NRCM中，过表达Macrod1能显著抑制PARP1的表达并恢复NAD⁺水平，进而激活SIRT3以抵御氧化应激。补充NAD⁺前体烟酸（50μM）可减轻PA刺激的心肌细胞的氧化应激。

研究人员发现，Macrod1通过抑制PARP1的表达减少了NAD⁺的消耗，从而激活了SIRT3和抗氧化应激信号。这项研究发现Macrod1是治疗DCM的新靶点。以PARP1-NAD⁺-SIRT3轴为靶点可能会为开发新的DCM干预策略开辟一条新途径。

附：英文原文

Title: Macrod1 suppresses diabetic cardiomyopathy via regulating PARP1-NAD+-SIRT3 pathway

Author: Liu, Yu-ting, Qiu, Hong-liang, Xia, Hong-xia, Feng, Yi-zhou, Deng, Jiang-yang, Yuan, Yuan, Ke, Da, Zhou, Heng, Che, Yan, Tang, Qi-zhu

Issue&Volume: 2024-03-08

Abstract: Diabetic cardiomyopathy (DCM), one of the most serious long-term consequences of diabetes, is closely associated with oxidative stress, inflammation and apoptosis in the heart. MACRO domain containing 1 (Macrod1) is an ADP-ribosylhydrolase 1 that is highly enriched in mitochondria, participating in the pathogenesis of cardiovascular diseases. In this study, we investigated the role of Macrod1 in DCM. A mice model was established by feeding a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). We showed that Macrod1 expression levels were significantly downregulated in cardiac tissue of DCM mice. Reduced expression of Macrod1 was also observed in neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA, 400μM) in vitro. Knockout of Macrod1 in DCM mice not only worsened glycemic control, but also aggravated cardiac remodeling, mitochondrial dysfunction, NAD+ consumption and oxidative stress, whereas cardiac-specific overexpression of Macrod1 partially reversed these pathological processes. In PA-treated NRCMs, overexpression of Macrod1 significantly inhibited PARP1 expression and restored NAD+ levels, activating SIRT3 to resist oxidative stress. Supplementation with the NAD+ precursor Niacin (50μM) alleviated oxidative stress in PA-stimulated cardiomyocytes. We revealed that Macrod1 reduced NAD+ consumption by inhibiting PARP1 expression, thereby activating SIRT3 and anti-oxidative stress signaling. This study identifies Macrod1 as a novel target for DCM treatment. Targeting the PARP1-NAD+-SIRT3 axis may open a novel avenue to development of new intervention strategies in DCM.

DOI: 10.1038/s41401-024-01247-2

Source: https://www.nature.com/articles/s41401-024-01247-2