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.

We tested the hypothesis that the de-endothelialized artery rings from the left anterior descending (LAD) coronary artery and its left ventricular branch (LVB) differ in their contractile responses to Na+–Ca2+-exchanger (NCX) mediated Ca2+-entry, muscarinic receptor activation with carbachol, and sarco/endoplasmic reticulum Ca2+ pump (SERCA) inhibition with thapsigargin. In LVB, the force of contraction (in N/g tissue) produced by the NCX mediated Ca2+-entry (17.5 ± 1.4) and carbachol (18 ± 1.5) was only slightly smaller than that due to membrane depolarization with KCl (24.0 ± 1.0). In contrast, in LAD the force of contraction produced with NCX (8.7 ± 0.7) and carbachol (6.1 ± 1.1) was much smaller than with KCl (15.7 ± 0.7). Thapsigargin also contracted LVB with greater force than LAD. When isolated microsomes were used, the binding to the muscarinic receptor antagonist quinuclidinyl benzilate was greater in LVB than in LAD. Microsomes were also used for Western blots. The intensities of signals for both SERCA and NCX were greater in LVB than in LAD. These biochemical observations were consistent with the contractile experiments. Thus, it appears that the differences between LAD and the resistance arteries may begin as early as LVB.