**6. Conclusions**

Remarkably, even if autophagy is not involved in apoptosis, probably contributes like a ben‐ eficial "eat-me" signal on the cell surface by exposing phosphatydylserine, necessary to the clearance by efferocytosis of apoptotic cells [154] (Figure 5). All these important findings suggest a potential efficacy for HDLs-based therapeutic opportunities in atherosclerosis.

42 Current Trends in Atherogenesis

**Figure 5.** Beneficial role of high density lipoproteins upstream ER stress and autophagy in endothelial cells. HDL- high density lipoprotein; LDL: low density lipoprotein; ox-LDL- oxidized lipoproteins; LC3-II- microtubule-associated pro‐

Recently an interesting study reported the peculiar expression on endothelial cells and macro‐ phages of a novel GRP78-interacting protein induced by ER stress, called Gipie [155]. Gipie be‐ longs to the Girdin family protein and is localized in the ER and Golgi apparatus in the endothelial cell lines (human umbilical vein endothelial cell-HUVEC and human coronary ar‐ tery endothelial cells-HCAEC), but not in epithelial or mesenchymal cells *in vitro*. The transfec‐ tion of Gipie into HUVEC cells exposed to ER inducer thapsigargin, a specific blocker of ER

Moreover the same protection was demonstrated by Gipie's over-expression in rat carotid artery endothelial cells after baloon injury, a well-known *in vivo* model of endothelial dam‐ age and restenosis. Finally also in adult P65 mice aorta, Gipie was superimposed with GRP78 in atheroprone sites like the inner curvature of the aortic arch, but not in the outer curvature or in the ascending aorta, less sensitive to hemodynamic stress. By interaction with GRP78, Gipie modulates IRE1/JNK signaling and CHOP expression, so reducing apop‐

tein1 light chain 3; CHOP- C/EBP homologous protein; JNK- c-Jun N-terminal kinase. Adapted from [154].

calcium ATP-ase pumps, was able to decrease CHOP expression and apoptosis.

Actually the pivotal role of ER stress response in atherosclerosis and cardiovascular diseases is widely accepted. Nevertheless it remains much work to do in particular to discover the multiple relationship between different integrated pathways associated to ER signaling and to maintain the best ER stress modulation in the endothelium and vascular wall. Indeed it is important to point out that in biology the UPR is considered a surviving mechanism, so its complete deregulation may not be useful but dangerous. However additional experimental studies are required to help identify novel therapies to restore proper ER homeostasis but in particular, those to stabilize the minority of dangerous plaques associated with acute cardio‐ vascular damage.
