Abstract
Protein disulfide isomerase (PDI) involves cell survival and death. Whether PDI mediates mechanical stretch stress (SS) and/or advanced glycosylation end products (AGEs) -triggered simultaneous increases in proliferation and apoptosis of vascular smooth muscle cells (VSMCs) is unknown. Here, we hypothesized that different expression levels of PDI trigger completely opposite cell fates among the different VSMC subtypes. Mouse veins were grafted into carotid arteries of non-diabetic and diabetic mice for 8 weeks; the grafted veins underwent simultaneous increases in proliferation and apoptosis, which triggered vein graft arterializations in non-diabetic or atherosclerosis in diabetic mice. A higher rate of proliferation and apoptosis was seen in the diabetic group. SS and/or AGEs stimulated the quiescent cultured VSMCs, resulting in simultaneous increases in proliferation and apoptosis; they could induce increased PDI activation and expression. Both in vivo and in vitro, the proliferating VSMCs indicated weak co-expression of PDI and SM-α-actin while apoptotic or dead cells showed strong co-expression of both. Either SS or AGEs rapidly upregulated the expression of PDI, NOX1 and ROS, and their combination had synergistic effects. Inhibiting PDI simultaneously suppressed the proliferation and apoptosis of VSMCs, while inhibition of SM-α-actin with cytochalasin D led to increased apoptosis and cleaved caspases-3 but had no effect on proliferation. In conclusion, different expression levels of PDI in VSMCs induced by SS and/or AGEs triggered a simultaneous increase in proliferation and apoptosis, accelerated vein graft arterializations or atherosclerosis, leading us to propose PDI as a novel target for the treatment of vascular remodeling and diseases.
Highlights
Cardiovascular diseases caused by hypertension, hyperglycemia and hyperlipidemia are the leading causes of morbidity and mortality in the clinic
Between the two rows of cells in the diabetic vein grafts there was an akaryotic area (Figures 1e–l) in which cells with strong co-expression of SM-α-actin (Figures 1g, h, k and l) and PDI (Figures 1i–l) could be found, indicating that akaryotic cells with a strong expression of SM-α-actin in the medium were dead vascular smooth muscle cells (VSMCs), which were closely associated with PDI overexpression while the cells in the medium of the non-diabetic vein grafts (Figure 1e) and the neointima and adventitia of the diabetic vein grafts (Figure 1f) represented weakly co-expressed SM-α-actin and PDI (Figures 1g–l), implying that strong co-expression of SM-αactin and PDI closely associated with cell death and weak co-expression of both relates to cell proliferation
These results suggest that PDI may mediate simultaneous increases in proliferation and apoptosis of VSMCs induced by SS, Advanced glycosylation end products (AGEs), or both via the downstream molecules, for example, NADPH oxidases-reactive oxygen species (ROS) signaling
Summary
Cardiovascular diseases caused by hypertension, hyperglycemia and hyperlipidemia are the leading causes of morbidity and mortality in the clinic. PDI is one of the members of the thioredoxin superfamily oxidoreductases, which includes about 20 subtypes,[13] in this system.[13,14,15] PDI gene knockout is lethal to cells and embryos.[16] PDI has three main functions: molecular chaperones, oxidoreductase and isomerase[13,17,18] and can promote the disulfide formation (oxidase), breakage (reductase) or rearrangement (isomerase) of oxidized proteins, which are directly involved in the regulation of endoplasmic reticulum stress,[15,19] oxidative stress,[20] resulting in the occurrence and development of many human major diseases, such as cancer, neurological degenerative changes, immune and viral infections and infertility.[14,19,21,22,23] PDI inhibition prevents an increase in the reduced form of PDI in human neuroblastoma SH-SY5Y cells treated by 1-methyl-4phenylpyridinium (MPP+), suppresses excessive protein folding, endoplasmic reticulum stress and induces clearance of aggregated α-synuclein in Parkinson’s disease by increased autophagy.[24] It has been reported that the expression levels and activity of PDI in the heart tissue of patients with hyperglycemia has been changed.[25] no data directly address whether the expression and activation of PDI in VSMCs are closely associated with the simultaneous increases in proliferation and apoptosis and whether VSMC phenotypes or subtypes in response to the same extracellular stimuli can influence it
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