Acid Sphingomyelinase Decreases Atherosclerotic Plaque Stability Monitored with Molecular Imaging

Abstract

Background: Acid sphingomyelinase (ASM) promotes atherogenesis and acute cardiovascular events. We previously demonstrated ASM inhibitor desipramine attenuated oxidized-LDL induced macrophage apoptosis in vitro. Here, we aim to determine whether ASM mediated apoptosis in plaque and improve stability in vivo. Methods: In this study, rabbits with abdominal aorta balloon injury and 12-week high-cholesterol diet (HCD) were used to simulate atherosclerotic plaque model. Atherosclerotic rabbits received oral administration of saline (Control group), atorvastatin (Ator group), or desipramine (DES group). ASM activity and ceramide level were measured by ultra-performance liquid chromatography (UPLC). Plaque morphology was assessed by histochemistry and immunohistochemistry. Apoptosis was evaluated by SPECT/CT imaging of 99mTc-duramycin uptake and TUNEL Results: We found that increasing ASM activity and ceramide level in atherosclerotic rabbits was abated by additional atorvastatin and desipramine treatment. Meanwhile, the DES and Ator groups were similar with regard to plaque stability, with smaller plaque size, areas of macrophages, higher smooth muscle cell content, and decreased apoptosis and matrix metalloproteinase (MMP) activities relative to the Control group. 99mTc-duramycin uptake of rabbit aorta was significantly higher in Control than in Normal group, while it was reduced by desipramine and atorvastatin administration. Moreover, uptake of 99mTc-duramycin positively correlated with apoptotic cell number, macrophage infiltration and plaque instability. Conclusion: The present study demonstrated that desipramine exerted plaque-stabilizing effects partially by suppressing apoptosis and MMP activity in rabbit model. And 99mTc-duramycin SPECT/CT imaging allowed noninvasively monitoring atherosclerotic disease and evaluating anti-atherosclerotic therapy. Funding Information: This work was supported by grants from the National Natural Science Foundation of China (No. 81901784 to ZM, No. 81170261 to ZGG). Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethics Approval Statement: All animal protocols were approved by the Committee of Animal Care and Use at Xiangya Hospital, Central South University, China. All procedures were conducted to minimize the number of animals used and their suffering.