Selenoprotein S Is Highly Expressed in the Blood Vessels and Prevents Vascular Smooth Muscle Cells From Apoptosis

Abstract

Atherosclerosis and related cardiovascular diseases (CVD) represent one of the greatest threats to human health worldwide. The protection of vascular smooth muscle cells (VSMCs) from apoptosis in the plaque has become an important therapeutic target for atherosclerotic plaque stabilization. A significant association of selenoprotein S (SelS) gene polymorphism with atherosclerotic CVD has been reported in epidemiologic studies, but the underlying mechanism remains unknown. In this paper, SelS expression in the thoracic aorta and its role in the protection of VSMCs from apoptosis have been studied. Western blot analysis showed that SelS was highly expressed in rat thoracic aorta. SelS gene silence by small interference RNA (siRNA) rendered VSMCs more sensitive to hydrogen peroxide- or tunicamycin- induced injury and apoptosis, as determined by MTT assay, Hoechst staining, and annexin V/propidium iodide staining. SelS silence aggravated hydrogen peroxide-induced oxidative stress and phosphorylation of p38 MAPK and c-Jun N-terminal kinase (JNK) in VSMCs. Furthermore, SelS silence enhanced endoplasmic reticulum (ER) stress induced by hydrogen peroxide or tunicamycin, as showed by the increased protein levels of ER chaperone 78 kDa glucose-regulated protein (GRP78), ER stress transducer phosphorylated protein kinase RNA like ER kinase (PERK), and the proapoptotic transcription factor C/EBP homologous protein (CHOP). In conclusion, the present study suggested that SelS highly expressed in the blood vessel might protect VSMCs from apoptosis by inhibiting oxidative stress and ER stress. Our finding provided mechanistic insights for the potential preventive role of SelS in atherosclerotic CVD.

Differential regulation of cellular stress responses by the endoplasmic reticulum-resident Selenoprotein S (Seps1) in proliferating myoblasts versus myotubes

“…Similar to our observations in C2C12 myoblasts, in proliferating rat primary VSMCs, Seps1 gene knockdown increased cellular susceptibility to oxidative and ER stress and was associated with activation of stress responsive signaling pathways (Ye et al. ). Whether Seps1 modulates cellular stress responses in differentiated VSMCs has to date not been determined.…”

“…This notion that Seps1 plays a role in modulating cellular stress responses in proliferating cells is further supported with increased ROS levels following Seps1 gene knockdown observed with other in vitro studies using primary vascular smooth muscle cells (Ye et al. ), HUVEC endothelial cells (Zhao et al. ), and porcine kidney epithelial 15 (PK15) cells (Gan et al.…”

“…Seps1 is highly expressed in blood vessels, in particular in vascular smooth muscle (Ye et al. ), and genetic studies of SEPS1 gene sequence polymorphisms have revealed an association with cardiovascular disease (Cox et al. ; Yu et al.…”

“…SEPS1 overexpression was also protective against oxidative stress in human umbilical vein endothelial cells (HUVECs) treated with H 2 O 2 (Zhao et al 2013). Accordingly, Seps1 gene knockdown was associated with increased reactive oxygen species (ROS), altered activity of primary antioxidant defense enzymes and reduced viability in HUVECs (Zhao et al 2013), HepG2 cells (Zeng et al 2008), and vascular smooth muscle cells (Ye et al 2016).…”

Endoplasmic Reticulum Stress in Arterial Smooth Muscle Cells: A Novel Regulator of Vascular Disease

“…SelS is abundantly expressed in ASMCs and silencing its expression was shown to sensitize the cells to ER stress and apoptosis [84]. Since apoptosis is a crucial mechanism of atherosclerosis progression, this provides an important treatment option.…”