Abstract
Xuezhikang (XZK), an extract of red yeast rice, is a traditional Chinese medicine widely used for the treatment of cardiovascular diseases in China and other countries. However, whether XZK treatment can improve atherosclerotic plaque stability is not fully understood. Based on our previously developed mouse model of spontaneous vulnerable plaque formation and rupture in carotid arteries in ApoE-/- mice. We showed that low-dose (600 mg/kg/d) XZK improved plaque stability without decreasing plaque area, whereas high-dose (1200 mg/kg/d) XZK dramatically inhibited vulnerable plaque progression accompanied by decreased plaque area. Mechanistically, XZK significantly suppressed lesional endoplasmic reticulum (ER) stress in mouse carotid arteries. In vitro, XZK inhibited 7-KC-induced activation of ER stress in RAW264.7 macrophages, as assessed by the reduced levels of p-PERK, p-IRE1α, p-eIF2α, c-ATF6, s-XBP1, and CHOP. Compared to controls, the XZK-treated group displayed dramatically decreased apoptotic cell numbers (shown by decreased TUNEL- and cleaved caspase3-positive cells), lower necrotic core area and ratio, and reduced expression of NF-κB target gene. In RAW264.7 cells, XZK inhibited 7-KC-induced upregulation of apoptosis, protein expression of apoptotic markers (cleaved caspase-3 and cleaved PARP), and NF-κB activation (shown by target gene transcription and IκBα reduction). Collectively, our results suggest that XZK effectively suppresses vulnerable plaque progression and rupture by mitigating macrophage ER stress and consequently inhibiting apoptosis and the NF-κB pro-inflammatory pathway, thereby providing an alternative therapeutic strategy for stabilizing atherosclerotic plaques.
Highlights
Atherosclerotic plaque destabilization and rupture with thrombosis is the central pathologic mechanism responsible for acute vascular events such as acute myocardial infarction and sudden coronary death[1, 2]
inositol-requiring enzyme 1α (IRE1α) (p-IRE1α), IRE1α, eIF2α, protein kinase RNA-like ER kinase (PERK) and IκBα were from Abcam (Cambridge, MA, USA); antibodies against BiP, phosphorylated PERK (p-PERK), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), spliced x-box binding protein 1 (s-XBP1), cleaved PARP, and active caspase-3 were from Cell Signaling Technology (Beverly, MA, USA); and antibodies against CCAAT-enhancer-binding protein homologous protein (CHOP) and activating transcription factor 6 (ATF6) were from Santa Cruz Biotechnology Inc. (Santa Cruz, CA, USA)
Compared to the control group, the treated mice exhibited a significantly decreased tendency to experience intraplaque hemorrhaging, a reduced incidence of vessel multilayer with discontinuity, and a lower incidence of plaque rupture with thrombus. These results indicate that XZK treatment protected ApoE-/- mice from vulnerable plaque progression and rupture as effectively as atorvastatin treatment
Summary
Atherosclerotic plaque destabilization and rupture with thrombosis is the central pathologic mechanism responsible for acute vascular events such as acute myocardial infarction and sudden coronary death[1, 2]. Mounting evidence suggests that excessive endoplasmic reticulum (ER) stress plays a significant role in atherosclerotic plaque progression, destabilization, and rupture[3]. To alleviate ER stress, cells activate the unfolded protein response (UPR). Prolonged activation of the UPR can lead to apoptosis and an inflammatory response[6, 7], both of which play key roles in plaque instability [8,9,10,11,12]. ER stress-inducing agents can accelerate atherosclerosis and promote pro-atherosclerotic cellular responses, including cholesterol accumulation, apoptosis, and activation of inflammatory pathways in vascular cells[17,18,19,20]. Targeting ER stress may represent a new promising therapeutic strategy for combating plaque instability and rupture
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