Esculeoside A attenuates aortic remodeling and early atherosclerosis-like changes, with protective effects strongly associated with Nrf2 activation in high-cholesterol-fed rats

Atherosclerosis is a progressive inflammatory and oxidative vascular disease, and the discovery of safe, natural therapeutic agents is becoming increasingly important. This study investigated the vascular protective effects of esculeoside A (ESA), a steroidal glycoside from Solanum lycopersicum, against atherosclerosis induced by a high-cholesterol diet (HCD) in rats, with a focus on the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) signaling axis. Male Wistar rats (n = 8/group) were assigned to control, ESA, HCD, HCD + ESA, or HCD + ESA + brusatol (an Nrf2 inhibitor, intraperitoneally) groups and treated daily for 8 weeks. ESA (100 mg/kg) was given orally, and brusatol (2 mg/kg) was injected intraperitoneally. Treatment with ESA significantly mitigated increases in serum cholesterol, triglycerides, LDL-c, and oxidized low-density lipoprotein (Ox-LDL-c) in HCD-fed rats. It also reduced aortic Ox-LDL-c levels in HCD rats by 51.3%. ESA also mitigated oxidative stress in these aortas, decreasing malondialdehyde (- 33.2%) and 8-hydroxy-2'-deoxyguanosine (- 63.1%), while enhancing antioxidant defenses, including superoxide dismutase (+ 111.2%), catalase (+ 185.1%), heme oxygenase-1 (HO-1) (+ 177.1%), and reduced glutathione (+ 144.7%). Aortic inflammation in HCD rats was significantly reduced, with tumor necrosis factor-alpha, interleukin-6, and nuclear factor kappa B expression decreasing by 66.5%, 69.6%, and 49.2%, respectively. ESA also attenuated aortic apoptosis in these HCD rats by reducing levels of Bcl-2-associated X protein, caspase-3, and cytochrome c, while upregulating Bcl-2. Mechanistically, ESA enhanced nuclear translocation of Nrf2 (+ 129.1%) in aortic tissue without affecting Keap1 expression. Within this HCD rat model, these vascular benefits occurred without significant changes in fasting glucose, insulin levels, or body weight. Notably, co-administration of brusatol abolished these effects, findings that are consistent with and strongly associated with Nrf2 activation; however, this mechanistic inference is based on pharmacologic inhibition. Collectively, ESA confers robust vascular protection against HCD-induced aortic remodeling and early atherosclerosis-like changes, with these effects being strongly associated with Nrf2 activation.