Department of Cardiovascular Medicine, Second Affiliated Hospital of Shantou University Medical College, No. 69, Dongxiabei Road, Shantou, Guangdong, China.
Department of Hematology and Oncology, Shenzhen Children's Hospital, 7019, Yi Tian Road, Shenzhen, Guangdong, China; Shenzhen Public Service Platform of Molecular Medicine in Pediatric Hematology and Oncology, Shenzhen, Guangdong, China; Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Mol Cell Endocrinol. 2019 Sep 15;495:110507. doi: 10.1016/j.mce.2019.110507. Epub 2019 Jul 14.
Clinical studies have demonstrated that cigarette smoking is strongly associated with insulin resistance and heart disease. Nicotine is considered the primary toxin constituent associated with smoking. However, the distinct molecular mechanism of nicotine-induced cardiac dysfunction remains unclear. Cardiomyocytes with nicotine-induced insulin resistance are characterized by decreased glucose uptake, as measured by 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose (2-NBDG), a fluorescent derivative of glucose, and reactive oxygen species (ROS) generation. Immunoblotting was used to evaluate the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), extracellular signal-related kinase (ERK) and phosphoinositide 3-kinase (PI3K, p85, Y607). We determined the impact of nicotine on insulin resistance and Nrf2, phospho-ERK and phospho-PI3K expression in the myocardial tissue of a mouse model. Nicotine increased ROS production and depressed insulin-induced glucose uptake in cardiomyocytes. Pretreatment with N-acetyl-L-cysteine (NAC), an antioxidant, reversed nicotine-inhibited glucose uptake induced by insulin. Nicotine exposure directly inhibited Nrf2 and increased ERK phosphorylation in cardiomyocytes, which were obstructed by NAC. Further exploration of signaling cascades revealed nicotine-induced ROS involved in inhibiting PI3K/Nrf2 and activating ERK in cardiomyocytes. Moreover, the mouse model treated with nicotine showed glucose intolerance and impaired insulin tolerance accompanied by inhibited PI3K/Nrf2 and increased ERK in myocardial tissues. Thus, nicotine induces insulin resistance via the downregulation of Nrf2 activity in cardiomyocytes, which is a potential mechanism of the pharmacological effects of nicotine. This study identified potential therapeutic targets against nicotine-related cardiovascular diseases.
临床研究表明，吸烟与胰岛素抵抗和心脏病密切相关。尼古丁被认为是与吸烟相关的主要毒素成分。然而，尼古丁引起的心脏功能障碍的独特分子机制尚不清楚。尼古丁诱导的胰岛素抵抗的心肌细胞的特征是葡萄糖摄取减少，如 2-[N-(7-硝基苯并-2-氧代-1,3-二唑-4-基)氨基]-2-脱氧-d-葡萄糖（2-NBDG），葡萄糖的荧光衍生物，和活性氧（ROS）的产生。免疫印迹用于评估核因子红细胞 2 相关因子 2（Nrf2）、细胞外信号调节激酶（ERK）和磷酸肌醇 3-激酶（PI3K，p85，Y607）的表达。我们确定了尼古丁对胰岛素抵抗和 Nrf2、磷酸化 ERK 和磷酸化 PI3K 在小鼠模型心肌组织中的表达的影响。尼古丁增加了 ROS 的产生，并抑制了心肌细胞中胰岛素诱导的葡萄糖摄取。抗氧化剂 N-乙酰-L-半胱氨酸（NAC）预处理逆转了尼古丁抑制的胰岛素诱导的葡萄糖摄取。尼古丁暴露直接抑制了心肌细胞中的 Nrf2 并增加了 ERK 的磷酸化，这被 NAC 阻断。对信号级联的进一步探索表明，尼古丁诱导的 ROS 参与抑制心肌细胞中的 PI3K/Nrf2 并激活 ERK。此外，用尼古丁处理的小鼠模型表现出葡萄糖不耐受和胰岛素耐受性受损，同时伴有心肌组织中 PI3K/Nrf2 的抑制和 ERK 的增加。因此，尼古丁通过下调心肌细胞中 Nrf2 的活性诱导胰岛素抵抗，这是尼古丁药理学作用的潜在机制。这项研究确定了针对尼古丁相关心血管疾病的潜在治疗靶点。
