Key Points
• Conclusion/Relevance: “ORAIP plays a role in the development of oxidative stress-induced atherosclerosis and may be an important therapeutic target for plaque rupture in patients with HeFH [heterozygous familial hypercholesterolemia].”
• The authors previously discovered an apoptosis-inducing ligand that was the post-translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A), which they term oxidative stress-responsive apoptosis-inducing protein (ORAIP). In the current study, the investigators examined the role of ORAIP in HeFH patients. In 60 HeFH patients, they assessed plasma ORAIP and oxidized low-density lipoprotein (oxLDL) levels, as well as 20 patients with LDL-C hypercholesterolemia.
• The investigators found that plasma levels of oxLDL were very high in patients with high concentrations of LDL-C—especially in those with HeFH. The ORAIP levels in HeFH grew to 10 times the normal range, and were related to maxLDL-C. The plasma ORAIP levels, however, did not appear to be influenced by diabetes or hypertension. Smoking significantly heightened the plasma ORAIP concentration. These results could be limited by small sample size. Of note, the researchers could not find a difference in plasma ORAIP levels in those with controlled vs uncontrolled LDL-C levels. Intriguingly, atherosclerosis and CVD risk significantly correlated with plasma ORAIP levels, thus suggesting that ORAIP could be an important residual risk factor.
• “Although the primary mechanism of oxidative stress induction in the arterial wall is unknown, ORAIP secreted from several cell types, including smooth muscle cells, at the site of oxidative stress in the coronary artery may induce apoptosis in susceptible cells with a high oxygen demand,” the authors wrote. “This may directly increase plaque vulnerability leading to plaque rupture. Because numerous factors may contribute to plasma ORAIP levels, the absence of a significant positive correlation between the plasma levels of ORAIP and max LDL-C, as well as oxLDL (data not shown) does not exclude the possibility that high LDL-C levels facilitate ORAIP secretion. Furthermore, infiltrating activated T-cells and macrophages in the atherosclerotic arterial lesions may injure the smooth muscle cells by secreting ORAIP as revealed in the present study.”