Nicotine induces insulin resistance via downregulation of Nrf2 in cardiomyocyte.

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.