Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China.
Acta Pharmacol Sin. 2024 Jun;45(6):1175-1188. doi: 10.1038/s41401-024-01247-2. Epub 2024 Mar 8.
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, 400 μM) 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 (50 μM) 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. Schematic illustration of macrod1 ameliorating diabetic cardiomyopathy oxidative stress via PARP1-NAD-SIRT3 axis.
糖尿病心肌病（DCM）是糖尿病最严重的长期后果之一，与心脏中的氧化应激、炎症和细胞凋亡密切相关。MACRO 结构域包含蛋白 1（Macrod1）是一种富含在线粒体中的 ADP-核糖基水解酶 1，参与心血管疾病的发病机制。在这项研究中，我们研究了 Macrod1 在 DCM 中的作用。通过喂养高脂肪饮食（HFD）和腹腔注射链脲佐菌素（STZ）建立 DCM 小鼠模型。我们表明，DCM 小鼠心脏组织中 Macrod1 的表达水平显著下调。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 Macrod1 表达减少。DCM 小鼠中 Macrod1 的敲除不仅恶化了血糖控制，还加重了心脏重构、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 部分逆转了这些病理过程。在 PA 处理的 NRCM 中，Macrod1 的过表达显著抑制了 PARP1 的表达并恢复了 NAD 水平，激活 SIRT3 以抵抗氧化应激。补充 NAD 前体烟酰胺（50μM）可减轻 PA 刺激的心肌细胞中的氧化应激。我们揭示 Macrod1 通过抑制 PARP1 表达来减少 NAD 消耗，从而激活 SIRT3 和抗氧化应激信号。这项研究确定 Macrod1 是治疗 DCM 的一个新靶点。靶向 PARP1-NAD-SIRT3 轴可能为 DCM 的新干预策略的开发开辟新途径。Macrod1 通过 PARP1-NAD-SIRT3 轴改善糖尿病心肌病氧化应激的示意图。
