Atherosclerosis, a complex disease that involves the accumulation of lipids, chronic inflammation, and vascular remodeling processes, is the leading cause of death and morbidity among adults in developed countries. Vascular endothelial cells (VECs) cover the internal surface of blood vessels and play an important role in maintaining vascular function [1,2]. It is widely acknowledged that oxidized low-density lipoprotein (oxLDL), a key inducer of atherosclerosis, causes endothelial injury, which is followed by accumulation of foam cells, inflammation, and proliferation of vascular smooth muscle cells in the plaque [[3], [4], [5]]. Meanwhile, numerous in vitro studies demonstrated that oxLDL could induce the derangement of the mitochondrial membrane potential, thus amplifying ROS production, ultimately leading to mitochondrial-dependent apoptosis in endothelial cells [[6], [7], [8]]. Nowadays, endothelial cell injury is confirmed as a frequent feature of early atherosclerotic lesions and vulnerable plaques, inhibition of oxLDL-induced endothelial cell injury might be an important strategy for reducing atherosclerosis [[9], [10], [11], [12]].

Caveolae are flask-shaped invaginations of the plasma membrane observed in various cell types and are particularly abundant in endothelial cells [13,14]. After the identification of caveolin-1(Cav-1) as the principal marker of caveolae, a growing body of evidence reveals that caveolae play major roles in the regulation of endothelial vesicular trafficking and signal transduction [[15], [16], [17], [18]]. In the endothelial cell luminal plasma membrane, the number of caveolae and its associated protein Cav-1 level could be locally affected by various atherogenic stimuli, thus favoring oxLDLs/LDLs infiltration or uptake in atherosclerosis-prone regions [[19], [20], [21]]. Meanwhile, LDL accumulation in atherosclerosis-prone areas was significantly reduced in Cav-1 deficient mice [16]. Moreover, the uptake of oxLDL, which Cav-1 mediates, could result in endothelial cell apoptosis [22]. Notably, recent studies reported that Cav-1 deletion suppressed atherosclerosis by attenuating LDL transcytosis and endothelial cell inflammation, suggesting Cav-1/caveolae was a central regulator that associated endothelial injury with atherosclerosis [16,17,[23], [24], [25]]. Besides caveolins, other proteins with scaffolding properties were exhibited additional relevant organizers of signal transduction at the caveolae [24,26]. Therefore, it is essential to explore the molecular components of the caveolae-associated signaling system in the endothelium of atherosclerosis.

Neuroendocrine long coiled-coil protein 2 (NECC2), also referred to as Jakmip3, is a novel long coiled-coil protein predominantly expressed in the central nervous system and endocrine tissues [27,28]. It has been confirmed that NECC2 is distributed in caveolae, wherein it colocalized with Cav-1 at the cell surface of PC12 cells and adipocytes. Interestingly, NECC2 regulated the NGF-mediated TrkA signaling pathway in PC12 cells and insulin signaling in adipocytes, suggesting that NECC2 may organize membrane microdomains specialized in signal transduction [28,29]. Although previous studies demonstrated that NECC2 might be involved in PC12 cell differentiation and adipocyte formation, the role and function of NECC2 in vascular endothelia cell has yet to be elucidated.

Recently, our research group identified a novel hydroxamic acid derivative (named YF-307) that could inhibit oxLDL-induced apoptosis in VECs. Using small molecular YF-307 combined with microarray assay, we found that oxLDL significantly up-regulated NECC2 expression of VEC, and YF-307 exhibited the opposite effects. In this research, we further explored whether NECC2 was involved in oxLDL-induced VEC injury and the development of atherosclerosis.