Department of Cardiology, Third Division, The Second Hospital of Hebei Medical University, No. 215 Heping Xi Road, Shijiazhuang, 050000, Hebei, China.
Clinical Medicine, Hebei Medical University, Shijiazhuang, Hebei, China.
ESC Heart Fail. 2023 Apr;10(2):1305-1313. doi: 10.1002/ehf2.14292. Epub 2023 Feb 1.
Myocardial infarction (MI) is one of the serious diseases with great mortality over the world. Myocardial mitochondrial oxidative stress has been implicated as a key player in MI. The histidine triad nucleotide-binding protein 2 (HINT2) is a nucleotide hydrolase and transferase located in mitochondria. HINT2 has multiple functions such as regulating mitochondrial lipid metabolism and respiration and glucose homeostasis. Although HINT2 has been shown to protect against MI, the underlying mechanisms were not fully elucidated. In this study, the effects of HINT2 on oxidative stress during MI were explored.
MI mouse models in both wild-type and HINT2-deficient mice were established. The expression of HINT2 in HINT2-deficient mice was determined by quantitative real-time PCR and western blot. The levels of oxidative stress were measured, including the levels of malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and glutathione (GSH). The myocardial functions, as indicated by left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS), were monitored. Both mRNA and protein expressions of HINT2 in the myocardial tissues were significantly down-regulated in MI mice starting at 6 h post-MI. MI induced oxidative stress 6 h post-MI in myocardial tissues of wild-type mice, as suggested by the enhanced MDA and NO levels and decreased SOD and GSH levels. The expression of HINT2 was negatively correlated to the MDA and NO levels and positively correlated to the SOD and GSH levels. HINT2-deficient MI mice had significantly elevated levels of MDA and NO and significantly decreased levels of SOD and GSH when compared with wild-type MI mice. HINT2-deficient MI mice had higher LVEDD and LVESD and lower LVEF and LVFS compared with wild-type MI mice, indicating that HINT2 deficiency exacerbated myocardial dysfunction.
HINT2 deficiency causes deteriorative oxidative stress in MI mice, leading to exacerbated myocardial dysfunction.
心肌梗死（MI）是全球死亡率较高的严重疾病之一。心肌线粒体氧化应激已被认为是 MI 的关键因素。组氨酸三联核苷酸结合蛋白 2（HINT2）是一种位于线粒体中的核苷酸水解酶和转移酶。HINT2 具有多种功能，如调节线粒体脂质代谢和呼吸以及葡萄糖稳态。尽管已经表明 HINT2 可以预防 MI，但其潜在机制尚未完全阐明。在这项研究中，探讨了 HINT2 在 MI 期间氧化应激中的作用。
建立了野生型和 HINT2 缺陷型小鼠的 MI 模型。通过定量实时 PCR 和 Western blot 测定 HINT2 缺陷型小鼠中 HINT2 的表达。测量氧化应激水平，包括丙二醛（MDA）、一氧化氮（NO）、超氧化物歧化酶（SOD）和谷胱甘肽（GSH）的水平。监测左心室舒张末期直径（LVEDD）、左心室收缩末期直径（LVESD）、左心室射血分数（LVEF）和左心室缩短分数（LVFS）等心肌功能。MI 后 6 小时，心肌组织中 HINT2 的 mRNA 和蛋白表达均明显下调。MI 诱导野生型小鼠心肌组织中氧化应激，表现为 MDA 和 NO 水平升高，SOD 和 GSH 水平降低。HINT2 的表达与 MDA 和 NO 水平呈负相关，与 SOD 和 GSH 水平呈正相关。与野生型 MI 小鼠相比，HINT2 缺陷型 MI 小鼠的 MDA 和 NO 水平显著升高，SOD 和 GSH 水平显著降低。与野生型 MI 小鼠相比，HINT2 缺陷型 MI 小鼠的 LVEDD 和 LVESD 更高，LVEF 和 LVFS 更低，表明 HINT2 缺乏加重了心肌功能障碍。
HINT2 缺乏导致 MI 小鼠的氧化应激恶化，导致心肌功能障碍加重。
