Peripheral arterial disease usually seriously affects the daily quality of life of patients and imposes huge personal and societal healthcare burdens [23, 24]. To the best of our knowledge, this is the first study to evaluate the association between serum Cyr61 levels and the risk of PAD. However, due to the cross-sectional nature of the study design, it is impossible to determine the causality between Cyr61 and PAD. Thus, we have to be careful about interpreting the associations concluded from this survey.
Potential biomarkers for diabetes with PAD
Considering the relevance of the disease, effective earlier screening and diagnosis of PAD for patients with diabetes has become increasingly important. However, there is still a lack of effective biomarkers with high sensitivity and specificity for early diagnosis, and often a patient consults the specialist when the disease is already significantly worsened. Several potential biomarkers were found to identify PAD in patients with diabetes. For instance, serum high mobility group box (HMGB) 1, fibroblast growth factor (FGF) 23 and osteopontin (OPN) have been correlated with the presence of PAD [25, 26]. In addition, thrombospondin-4 (TSP-4) levels were significantly increased with PAD severity in patients with concomitant diabetes and could be a novel marker of atherosclerotic activity [27]. Recently, the association between circulating serum growth differentiation factor (GDF) 15 and lower extremity atherosclerotic disease (LEAD) has been investigated in Chinese diabetes subjects [28]. Furthermore, Hayashi, A. et al. reported a method for accurate skin temperature measurement using noncontact, handheld infrared skin thermometer, which could serve as a new, cost-effective screening strategy for earlier diagnosis of PAD [29]. Very recently, Biscetti and colleagues reported that elevated plasma sortilin is significantly and independently associated with the presence of lower limb PAD in statin-free patients with diabetes, while omentin-1 is reduced in the same population. Both of them could be promising markers for clinically significant atherosclerosis in the lower limbs [30, 31].
Cyr61 and peripheral vascular injuries
Cyr61 is a multifunctional matricellular protein that plays essential roles in regulating inflammation, wound healing and fibrogenesis in adults. Aberrant Cyr61 expression is associated with numerous pathologies, including diseases associated with autoimmune, metabolism and chronic inflammation [32]. Furthermore, regulation of the Cyr61 level in the circulation and vital organs has also been observed during experimentally induced sepsis [33, 34]. In terms of peripheral vascular disease, previous studies have demonstrated that Cyr61 is overexpressed in vascular smooth muscle cells of atherosclerotic lesions both in humans and in animal models [21, 35, 36] and could stimulate adhesion of vascular smooth muscle cells in a dose-dependent manner [12]. Interestingly, plasminogen (Plg)-mediated Cyr61 cleavage and activation promoted endothelial cell migration and neovascularization in vitro and in vivo. Targeting Plg/Cyr61 may offer exciting therapeutic opportunities for strengthening mesenchymal stem cells therapy in ischemic diseases [37]. Because the concept that inflammation participates pivotally in the pathogenesis of atherosclerosis has gained considerable attention [38], we speculated that chronic low-grade inflammation, together with the increased Cyr61 concentration contribute, at least in part, to the occurrence of atherosclerotic lesions of the lower limbs in patients with diabetes. In the present study, we found that serum Cyr61 levels increase according to severity of PAD, as if there were a dose-dependent relationship. Furthermore, results of ROC curve analysis show that Cyr61 concentrations can effectively identify the presence of PAD in subjects with diabetes, and the diagnostic sensitivity and specificity are better than the ABI. Thus, serum Cyr61 may be a promising biomarker for early diagnosis and effective follow-up of PAD in patients with diabetes.
It is not possible to definitively clarify whether Cyr61 levels are a cause or an effect of PAD, or even both, through a vicious cycle. In fact, earlier studies on Cyr61 highlighted its causative roles in intima proliferation. For instance, negative regulation of the Cyr61 gene led to the inhibition of vascular smooth muscle cell proliferation and neointimal hyperplasia [12]. Matsumae and colleagues also demonstrated that knockdown of Cyr61 significantly suppressed neointimal hyperplasia in a rat carotid artery balloon injury model [17]. Thus, targeting circulating Cyr61 may provide a novel strategy for the prevention of peripheral arterial disease.
Limitations
The study has several major limitations that should be noted. First, due to the cross sectional design of the study, we could not establish a causal relationship between serum Cyr61 and the development of PAD. Nevertheless, our results support the hypothesis that Cyr61 is important in peripheral atherosclerosis physiopathology. Second, the cross-sectional measurements may not represent the participant’s stable level of serum Cyr61. Therefore, the results of this study should be interpreted with caution. Third, the enrolled individuals were hospitalized patients with diabetes in the Suzhou area (Jiangsu, China), and the generalizability of the results to other diabetic populations needs to be tested. A further limitation is that we need prospective data to confirm whether higher Cyr61 levels may suffice as an effective biomarker for PAD in patients with diabetes. Last, because the enrolment of participants was restricted to patients with T2DM with higher susceptibility for developing PAD, selection bias of the study was an inevitable and non-negligible issue. In addition, we did not use healthy controls to determine the normal level of Cyr61. In fact, there is still a lack of studies which focused on differences of Cyr61 levels among health populations due to aging, ethnic variation, genetic background , and nutritional status. We believe that our results can provide a valuable reference for future large-scale studies.