Cystatin C–Adiponectin Complex in Plasma Associates with Coronary Plaque Instability

Abstract

Aim: Adiponectin (APN) is an adipocyte-derived bioactive molecule with antiatherogenic properties. We previously reported that cystatin C (CysC) abolished the anti-atherogenic effects of APN. We aimed to elucidate the clinical significance of CysC–APN complex in patients with coronary artery disease (CAD).Methods: We enrolled 43 stable CAD male patients to examine the relationship between CysC–APN complex and coronary plaque characteristics. Serum was immunoprecipitated by the anti-APN antibody and immunoblotted by the anti-CysC antibody to demonstrate the presence of CysC–APN complexes in vivo. To confirm their binding in vitro, HEK293T cell lysates overexpressing myc-APN and FLAG-CysC were immunoprecipitated with an anti-myc or anti-FLAG antibody, followed by immunoblotting with an anti-APN or anti-CysC antibody.Results: CysC was identified as a specific co-immunoprecipitant with APN by the anti-APN antibody in human serum. In vitro, FLAG-CysC was co-immunoprecipitated with myc-APN by the antimyc antibody and myc-APN was co-immunoprecipitated with FLAG-CysC by the anti-FLAG antibody. Among CAD patients, serum CysC–APN complex levels negatively correlated with fibrotic components of coronary plaques and positively correlated with either necrotic or lipidic plus necrotic components. Plaque burden negatively correlated with serum APN levels but not serum CysC–APN complex levels. Serum CysC levels had no association with plaque characteristics. In multivariate analysis, CysC–APN complex levels were identified as the strongest negative factor for fibrotic components and the strongest positive factor for both necrotic and lipidic plus necrotic components.Conclusion: Measuring serum CysC–APN complex levels is helpful for evaluating coronary plaque instability in CAD patients.

High Plasma Levels of Legumain in Patients with Complex Coronary Lesions

“…Angiography cannot visualize plaques and shows only the severity and morphology of stenotic lesions. However, in our study, intravascular ultrasound (IVUS) or optical coherence tomography (OCT), which can visualize coronary plaques and evaluate plaque characteristics 32 ) , were not always performed. Second, we did not measure blood legumain levels in the coronary sinus.…”

Niacin action in the atherogenic mixed dyslipidemia of metabolic syndrome: Insights from metabolic biomarker profiling and network analysis

“…44 Of the remaining biomarkers identified by regression network analysis at high stringency, the adiponectincystatin C cluster was notable, particularly in view of the recent finding that these proteins are complexed in plasma. 45 The finding that cystatin C is an inhibitor of adiponectin-mediated vasculoprotective effects suggests that the marked increment in adiponectin levels seen on niacin (72%), and thus its potential biological actions, were largely neutralized by complexation with cystatin C. 45 This effect is of considerable relevance to the potential attenuating impact of niacin on the pathophysiology of cardiometabolic disease, as adiponectin is an insulin sensitizer, modulates inflammatory responses, and promotes macrophage polarization to the antiinflammatory M2 phenotype. 46 Indeed, the induction of insulin resistance by ER niacin in this MetS cohort was not attenuated by major increment in adiponectin (Table 1).…”

Atheroprotective Roles of Adiponectin via CCL2 Inhibition

“…Particularly, AdipoR1 and AdipoR2, the cell membrane-bound receptors of APN, are involved in insulin sensitivity and antidiabetic effects, whereas calreticulin promotes the removal of apoptotic cells via binding to APN. We have reported several APN-associating molecules, ESL-1 22) , CysC 23) , and…”

“…Recently, we determined several APN-interacting molecules, E-selectin ligand-1 (ESL-1) 22) , cystatin C (CysC) 23) , and Mac-2 binding protein (M2BP) 24) , and we demonstrated that the functions of APN and its interacting molecules are mutually regulated. Moreover, the possible interaction between APN and several chemokines was suggested in a previous report 25) .…”