Deficiency of TDAG51 Protects Against Atherosclerosis by Modulating Apoptosis, Cholesterol Efflux, and Peroxiredoxin‐1 Expression

Abstract

BackgroundApoptosis caused by endoplasmic reticulum (ER) stress contributes to atherothrombosis, the underlying cause of cardiovascular disease (CVD). T‐cell death‐associated gene 51 (TDAG51), a member of the pleckstrin homology‐like domain gene family, is induced by ER stress, causes apoptosis when overexpressed, and is present in lesion‐resident macrophages and endothelial cells.Methods and ResultsTo study the role of TDAG51 in atherosclerosis, male mice deficient in TDAG51 and apolipoprotein E (TDAG51−/−/ApoE−/−) were generated and showed reduced atherosclerotic lesion growth (56±5% reduction at 40 weeks, relative to ApoE−/− controls, P<0.005) and necrosis (41±4% versus 63±8% lesion area in TDAG51−/−/ApoE−/− and ApoE−/−, respectively; P<0.05) without changes in plasma levels of lipids, glucose, and inflammatory cytokines. TDAG51 deficiency caused several phenotypic changes in macrophages and endothelial cells that increase cytoprotection against oxidative and ER stress, enhance PPARγ‐dependent reverse cholesterol transport, and upregulate peroxiredoxin‐1 (Prdx‐1), an antioxidant enzyme with antiatherogenic properties (1.8±0.1‐fold increase in Prdx‐1 protein expression, relative to control macrophages; P<0.005). Two independent case–control studies found that a genetic variant in the human TDAG51 gene region (rs2367446) is associated with CVD (OR, 1.15; 95% CI, 1.07 to 1.24; P=0.0003).ConclusionsThese findings provide evidence that TDAG51 affects specific cellular pathways known to reduce atherogenesis, suggesting that modulation of TDAG51 expression or its activity may have therapeutic benefit for the treatment of CVD.

Endoplasmic reticulum stress inhibition reduces hypertension through the preservation of resistance blood vessel structure and function

“…Superoxide generation was measured, as previously, with dihydroethidium (DHE) staining technique [16,30] in rat VSMC treated for 18 h with the endoplasmic reticulum stress inducer tunicamycin (1 mg/ml), the endoplasmic reticulum stress inhibitor 4-PBA (1 mmol/l) or tunicamycin in combination with 4-PBA. Images were captured as described above.…”

Regulation of PHLDA1 Expression by JAK2-ERK1/2-STAT3 Signaling Pathway

“…However, another study showed that PHLDA1 played no role in T‐cell apoptosis [Oberg et al, ]. Furthermore, it was reported to have a different function including atherogenesis regulation [Hossain et al, , ], and follicular stem cell marker [Sellheyer and Krahl, ]. Basseri et al suggested that PHLDA1 is involved in energy homeostasis, at least in part, by regulating lipogenesis in liver, and white adipose tissue [Basseri et al, ].…”

4‐Phenylbutyrate protects against atherosclerotic lesion growth by increasing the expression of HSP25 in macrophages and in the circulation of Apoe −/− mice

“…Mouse tissue samples were prepared as previously described by Hossain et al (24). Briefly, following fixation with 10% neutral buffered formalin, hearts were embedded in paraffin.…”

“…Immunohistochemical staining of atherosclerotic lesions was performed as previously described (9,24,25). Tissue was fixed with formalin and embedded in paraffin.…”