The Nrf2/HO-1 signaling pathway has been recognized as important for the oxidative stress response. As a member of the heme oxygenase family, HO-1 plays a vital role in anti-inflammatory, antioxidant, and antiapoptotic processes. Following oxidative or electrophilic stress, the Keap1 protein dissociates from Nrf2, leading to Nrf2 translocation into the nucleus and the production of antioxidant enzymes such as catalase, glutathione (GSH), superoxide dismutase (SOD), and heme oxygenase-1 (HO-1). In the physiological state, Nrf2 is bound to Kelch-like ECH-associated protein 1 (Keap1), which functions as a negative regulatory factor of Nrf2 and localizes in the cytoplasm, where it activates the process of ubiquitin-mediated degradation. The Nfe2l2 gene encodes nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor responsible for regulating the cellular redox balance and protective antioxidant and phase II detoxification responses in mammals. Oxidative stress has been identified as one of the key factors contributing to the development of cardiac hypertrophy. Recently, many studies have found that sympathetic stress is often associated with increased levels of reactive oxygen species (ROS). Isoproterenol (ISO), a nonselective β-adrenergic receptor agonist, has been reported to induce cardiac hypertrophy and is recognized as one of the classic animal models. Activation of the β-adrenergic receptor is an important contributor to sympathetic nerve excitation, and it is closely related to heart function. Sympathetic nerve activation is considered one of the main causes of myocardial hypertrophy. It is strongly associated with an increased risk of many cardiovascular diseases, such as heart failure, sudden death, and arrhythmia. Myocardial hypertrophy is characterized by myocyte hypertrophy, fibroblast activation, and extracellular matrix accumulation, an adaptive response to processes such as mechanical and neurohumoral stimulation. XJEK ameliorates MH by activating the Nrf2/HO-1 signaling pathway, suggesting that XJEK is a potential treatment for MH. XJEK-induced oxidative stress may be related to potentiating Nrf2 nuclear translocation and HO-1 expression compared with the MH groups. XJEK also suppressed the decreased superoxide dismutase (SOD) and catalase (CAT) activities and increased malondialdehyde (MDA) levels in serum of mice with MH. XJEK administration also improved MH, as evidenced by decreased atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain ( β-MHC) levels. XJEK administration markedly ameliorated cardiovascular remodeling (CR), as manifested by a decreased HW/BW ratio and CSA and less collagen deposition after MH. On the eighth day after drug treatment, electrocardiogram (ECG) and echocardiography were performed, the mice were sacrificed, and blood and heart tissues were collected for further analysis. Forty SPF male Kunming mice were randomized into 5 groups ( n = 8 mice per group): control group, MH group, MH + different doses of XJEK (7.5 g/kg/day and 10 g/kg/day), and MH + metoprolol (60 mg/kg/day). We hypothesized that XJEK may prevent isoproterenol (ISO)-induced myocardial hypertrophy (MH) in mice by ameliorating oxidative stress (OS) through a mechanism that may be related to the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1(HO-1) pathways. Xin-Ji-Er-Kang (XJEK) inhibited cardiovascular remodeling in hypertensive mice in our previous studies.
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