Role of NADPH oxidase 2-derived reactive oxygen species in cardiac electrophysiological disorders

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  Figure 1.. Mechanism of NOX2 activation and ROS generation in the heart under pathological conditions. Under physiological conditions, ROS production is tightly balanced by antioxidant defense systems. Pathological stimuli, including pressure/volume overload, hypoxia/ischemia, diabetes/obesity, and tachypacing, disrupt this balance. These signals, including Ang II, growth factors, cytokines, and mechanical forces, activate receptor-mediated signaling pathways, including PI3K/AKT, PKC, and MAPK. These kinases phosphorylate the cytosolic subunits of NOX2 (p47phox, p67phox, p40phox) and promote the translocation of the Rac1/2 GTPase, leading to the assembly of the functional NOX2 complex at the membrane. The assembled complex catalyzes the conversion of NADPH to NADP+ +H+, driving ROS production. ROS, reactive oxygen species; Ang II, angiotensin II; PI3K, phosphoinositide-3-kinase; AKT, protein kinase B; PKC, protein kinase C; MAPK, mitogen-activated protein kinases.

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  Figure 2.. Mechanisms by which NOX2-derived ROS promote atrial fibrillation. Following activation by upstream pathological signals, NOX2 generates ROS, driving arrhythmogenic remodeling through multiple pathways. Structurally, NOX2-mediated ROS activate JNK2, downregulate connexins Cx40 and Cx43, disrupt intercellular electrical coupling, and provide a structural substrate for reentry. At the electrophysiological level, ROS differentially regulate ion channels either directly or via activating downstream kinases, such as PKC and CaMKII: they suppress INa and ICa,L, while enhancing IKur, IKACh, and IKs. These changes collectively shorten atrial APD and ERP, promoting the maintenance of reentry. Furthermore, NOX2–ROS signaling directly oxidizes the RyR2, or activates CaMKII via oxidation, which can also be phosphorylated or transcriptionally upregulated by JNK2. CaMKII phosphorylates RyR2 and triggers diastolic SR Ca2+ leak. Elevated cytosolic Ca2+ activates NCX, generating ITi that induces DADs. Activated CaMKII also enhances INa,L, evoking EADs. These abnormalities, including aberrant Ca2+ handling, impaired ion channel function, and structural remodeling, collectively create a…

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  Figure 3.. Schematic illustration of NOX2-mediated oxidative stress in ventricular arrhythmogenesis. Mechanical forces activate NADPH oxidase 2 (NOX2) to generate stretch-induced reactive oxygen species (ROS), termed X-ROS, which modulates cardiomyocyte excitation-contraction coupling under physiological conditions. In pathological states, ROS oxidizes Ca2+/calmodulin-dependent protein kinase II (CaMKII) to enhance ryanodine receptor 2 (RyR2) activity, triggering sarcoplasmic reticulum (SR) Ca2+ leak and elevated diastolic Ca2+ levels, which in turn induce delayed afterdepolarizations (DADs) via the sodium-calcium exchanger (NCX)-mediated transient inward current (ITi). Additionally, risk factors such as high-fat diet, hyperglycemia, ethanol, epinephrine, tachycardia, and angiotensin II (ang II) activate NOX2 to generate ROS, remodeling cardiac ion channels by suppressing transient outward potassium current (Ito)and upregulating late sodium current (INa,L)and L-type calcium current (ICa,L), thereby inducing early afterdepolarizations (EADs). Furthermore, ROS modulate sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA)-mediated Ca2+ uptake and mitochondrial redox status, exacerbating…