Dipeptidyl peptidase-4 inhibition targeting vascular senescence as a novel treatment for atherosclerosis
Journal
Journal of diabetes investigation
Date Issued
2024
Author(s)
Abstract
In the article by Herman et al.1, the importance of dipeptidyl peptidase-4 (DPP4) in senescent vascular smooth muscle cells (VSMCs) and atherosclerosis is highlighted. In senescent VSMCs, the expression of DPP4 was higher and correlated with enhanced expression of senescence-associated secretory phenotype (SASP) factors, especially several complement and coagulation factors. By knocking-down DPP4 or an DPP4 inhibitor, the study showed their effects on senescent VSMCs and atherosclerosis. First, inhibition of DPP4 promoted cell death of senescent VSMCs, at least partly through the regulatory effect on complement and coagulation factors. In the atherosclerotic mouse model, the administration of the DPP4 inhibitor restored the reduced tail-bleeding time by high-fat diet and the coagulation phenotype, decreased the expression of SASP and the number of senescent cells in aorta, and increased the plaque stability. In addition, using single-cell sequencing analysis, the authors have identified two clusters of VSMCs with high DPP4 expression. These DPP4-expressing VSMCs also expressed senescent markers and inflammatory marker, and DPP4 inhibitor could suppress the expression of the complement and coagulation factors, as well as several factors critical for cell survival in one of the two clusters of DPP4-expressing senescent VSMCs. VSMC senescence is a novel pathophysiology of atherosclerosis, and is commonly observed in atherosclerotic plaques2. VSMC senescence can be induced by various cardiovascular risk factors, such as diabetes, hyperlipidemia and smoking, and generation of reactive oxygen species is one of the most important pathophysiological links. Senescent cells show a distinct phenotype and can secret various SASP factors, including pro-inflammatory cytokines, chemokines, matrix metalloproteinases (MMPs), complement and coagulation factors, and other factors. The compositions of the SASP factors are different in different cell types, and these SASP factors act in both autocrine and paracrine manners, influencing the senescent cell itself, as well as the surrounding microenvironment. In the literature, SASP factors are involved in various diseases, such as pulmonary hypertension, atherosclerosis, aortic aneurysm and others. In atherosclerosis, SASP plays a role in plaque instability by promoting mitochondrial reactive oxygen species production, secreting matrix-degrading proteases that contribute to fibrous cap thinning and participating in chronic inflammation associated with atherosclerosis. Therefore, targeting VSMC senescence or SASP has been proposed as a novel strategy for the treatment of vascular diseases in recent years. Treatment strategies targeting senescent cells are called senotherapies3, which encompass two distinct approaches. The first approach involves the use of senolytic agents to induce apoptosis in senescent cells and eliminate these cells from the tissue. The second approach utilizes senomorphic agents, which aim to modulate or attenuate the expression of SASP factors, leading to senostasis, a state where the harmful effects of SASP are reduced. Several agents have been proposed as having clinical potential for senolysis or senomorphic effects in atherosclerosis. In this article, DPP4 inhibition is first proposed as a senotherapy1. The study showed that there is an elevation in both the amount of surface DPP4 and the expression level of DPP4 messenger ribonucleic acid in senescent VSMCs. Furthermore, the research has established a causal relationship between DPP4 and senescence cell survival, and has proved that DPP4 inhibition could induce cell death of the senescent VSMCs, suggesting that DPP4 inhibition has a senolytic effect. In addition, they also provide evidence for DPP4 inhibition as a senomorphic therapy. Based on their data, DPP4 could contribute to senescence cell survival through the modulation of downstream targets, specifically coagulation-related factors, such as coagulation factor II, matrix metalloproteinase-1, tissue-type plasminogen activator and Serpin D1; whereas DPP4 inhibition could downregulate the activated SASP factors, especially the complement and coagulation factors. Taken together, these data suggest that DPP4 inhibition could impair the senohemostasis of VSMCs by both senolytic and senomorphic effects, and improve plaque stability in atherosclerotic mice. Interestingly, the authors of the study have utilized single-cell ribonucleic acid sequencing technique to identify two subsets of senescent VSMCs that respond to DPP4 inhibition1. The single-cell ribonucleic acid sequencing analysis showed that the cell cluster with the highest expression of DPP4 exhibited a transcriptomic pattern consistent with senescence, especially the expression of proteins related to p53 signaling and cell survival, and the complement and coagulation factors. DPP4 inhibition could strongly suppress the expression of these SASP factors. Therefore, the response of this cell cluster might be the key of the senomorphic effect of the DPP4 inhibitor. In contrast, there was another cell cluster with the second-highest DPP4 expression, which also showed markers of senescence. Different from the previous cell cluster, this cell cluster lacked the expression of several traditional smooth muscle contractile markers, but had an increased expression of proteins related to T-cell recruitment and monocyte activation, suggesting that these cells could be dedifferentiated into inflammatory, potentially senescent VSMCs. Treatment with DPP4 inhibitors resulted in a significant reduction in the number of cells in this cluster, indicating a that these cells could potentially be responsible for the senolytic effect of DPP4 inhibitors. In humans, it is worth noting that several cardiovascular outcome trials have been carried out for DPP4 inhibitors4, such as saxagliptin (Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus), sitagliptin (Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes), linagliptin (Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk) and alogliptin (Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes). Nevertheless, none of these trials showed a cardiovascular benefit associated with the use of DPP4 inhibitors, which is different from findings in animal studies including this study1. There are several possible reasons for the discrepancy between human and animal studies. First, the DPP4 inhibitor used in the study1, vildagliptin, did not have a cardiovascular outcome trial in humans. As different DPP4 inhibitors might have different effects on atherosclerosis, the choice of DPP4 inhibitor might be a factor for the difference. Second, it is important to note that vildagliptin was administered at a dose of 10 mg/kg/day in the study, whereas the dose of vildagliptin used in humans is 50 mg/day. Theoretically, the doses used in mice were different from that in humans, using different conversion equations5. This might also contribute to the different effects between humans and mice. Third, in human cardiovascular outcome trials, DPP4 inhibitors were given to patients who had type 2 diabetes for many years, and some of the patients already had atherosclerotic diseases. In contrast, DPP4 inhibitors were given earlier in animal studies, and were mostly given along with a high-cholesterol diet. Therefore, the potential cardiovascular protection observed with DPP4 inhibitors in animal studies might be attributed to their early use. In addition, the duration of DPP4 inhibitors used in animal and human studies were different. In summary, the differences in the choice of DPP4 inhibitors, dose, duration and timing of initiation of DPP4 inhibitors, in addition to organism difference, might contribute to the different results of DPP4 inhibitors on atherosclerotic cardiovascular diseases, which warrants further research. In conclusion, senotherapy is a novel treatment strategy for atherosclerotic diseases. DPP4 inhibition has been shown to be both senolytic and senomorphic. It can induce the death of senescent VSMCs and suppress the expression of several SASP, especially the complement and coagulation factors. As a result, DPP4 inhibition can increase plaque stability in the atherosclerotic animal model. In the future, translational research and clinical trials based on the findings should be carried out to further investigate the effect of this novel strategy for the treatment of atherosclerosis. Hung-Yuan Li is an Editorial Board member of Journal of Diabetes Investigation and a co-author of this article. To minimize bias, he was excluded from all editorial decision-making related to the acceptance of this article for publication.
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Type
journal article