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Esculeoside A attenuates aortic remodeling and early atherosclerosis-like changes, with protective effects strongly
Talal Abdulaziz Alfurayh1, Abu ElGasim A Yagoub1, Ghedeir M Alshammari2
1Department of Food Sciences and Nutrition, College of Food and Agricultural Sciences, King Saud University, P.O. Box 2460, 11451, Riyadh, Saudi Arabia.
Abstract:
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.
Insights
Esculeoside A (ESA) offers significant vascular protection against high-cholesterol diet-induced atherosclerosis in rats. This natural compound activates the Nrf2 pathway, reducing oxidative stress and inflammation in the aorta.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Natural Product Chemistry
Background:
- Atherosclerosis is a major cause of cardiovascular disease, characterized by inflammation and oxidative stress.
- There is a growing need for safe, natural therapeutic agents to combat atherosclerosis.
- The Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) signaling pathway plays a crucial role in cellular defense against oxidative stress.
Purpose of the Study:
- To investigate the vascular protective effects of esculeoside A (ESA), a steroidal glycoside from Solanum lycopersicum.
- To determine if ESA's protective effects against high-cholesterol diet (HCD)-induced atherosclerosis in rats involve the Keap1/Nrf2 signaling axis.
Main Methods:
- Male Wistar rats were fed a high-cholesterol diet (HCD) and treated with ESA (100 mg/kg, orally) or brusatol (Nrf2 inhibitor, 2 mg/kg, intraperitoneally) for 8 weeks.
- Vascular protective effects were assessed by measuring serum lipids, aortic lipid deposition, oxidative stress markers, inflammatory markers, and apoptosis.
- Keap1/Nrf2 pathway activation was evaluated by assessing Nrf2 nuclear translocation in aortic tissue.
Main Results:
- ESA treatment significantly reduced serum cholesterol, triglycerides, LDL-c, and oxidized LDL-c in HCD rats.
- ESA mitigated aortic oxidative stress and inflammation, decreasing markers like malondialdehyde, 8-hydroxy-2'-deoxyguanosine, TNF-α, IL-6, and NF-κB.
- ESA enhanced antioxidant defenses (SOD, catalase, HO-1, GSH) and attenuated apoptosis by modulating Bcl-2 family proteins and caspases, consistent with Nrf2 activation.
Conclusions:
- Esculeoside A confers robust vascular protection against HCD-induced atherosclerosis-like changes in rats.
- These protective effects are strongly associated with the activation of the Nrf2 signaling pathway.
- ESA represents a promising natural therapeutic agent for managing atherosclerosis.
