Plasma Levels of Proprotein Convertase Subtilisin/Kexin Type 9 Are Elevated in Patients With Peripheral Artery Disease and Associated With Metabolic Disorders and Dysfunction in Circulating Progenitor Cells

Abstract

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in cholesterol homeostasis, inflammation, and oxidative stress. This study investigated the association of plasma PCSK9 levels with the presence and severity of peripheral artery disease (PAD) and with parameters of endothelial homeostasis.Methods and ResultsA post hoc analysis of 2 randomized trials (115 patients, 44 with PAD and 71 without atherosclerotic disease) was conducted. Patients with PAD had significantly higher plasma PCSK9 levels than those without (471.6±29.6 versus 302.4±16.1 ng/mL, P<0.001). Parameters for glucose homeostasis, endothelial progenitor cell functions, apoptotic circulating endothelial cell counts, and plasma levels of vascular endothelial growth factor–A165 and oxidized low‐density lipoprotein were correlated with PCSK9 concentration. By multivariable linear regression analysis, presence of PAD, plasma glucose or hemoglobin A1c levels, apoptotic circulating endothelial cell counts, and vascular endothelial growth factor–A165 concentration were found to be associated with PCSK9 levels after multivariable adjustment. Patients with extensive involvement of PAD or with severe PAD had significantly higher PCSK9 levels than those without PAD. Computed tomographic angiography showed that the numbers of chronic total occlusion sites and vessels involved were positively associated with PCSK9 levels in patients with PAD (r=0.40, P=0.01, and r=0.36, P=0.02, respectively).Conclusion PCSK9 levels were significantly higher in patients with PAD, especially those with advanced PAD. Further large‐scale studies examining the effect of PCSK9‐targeting therapies or the modification of PCSK9 levels on cardiovascular outcomes in this clinical setting are warranted.Clinical Trial RegistrationCohort 1: URL: ClinicalTrials.gov. Unique identifier: NCT01952756; cohort 2: URL: ClinicalTrials.gov. Unique identifier: NCT02194686.

High Serum PCSK9 Is Associated With Increased Risk of New-Onset Diabetes After Transplantation in Renal Transplant Recipients

“…In renal patients, PCSK9 has been documented to be elevated proportional to the degree of proteinuria (24) but to be unaffected by moderately compromised renal function (25). In the current RTR cohort, PCSK9 was increased in conjunction with (central) obesity, as observed in nonrenal populations (26)(27)(28). Thus, although we did not enroll a control group, serum PCSK9 levels appeared to be elevated in a considerable number of RTRs.…”

“…This relationship emphasizes the necessity to adjust for statin use in multivariable analysis regarding the association of PCSK9 with NODAT. In keeping with data in nonrenal populations (24,26,28,29), serum PCSK9 was associated with triglycerides, which we also controlled for in the analysis. Moreover, in keeping with earlier reports (26,30), serum PCSK9 was positively associated with HOMA-IR, which is a known predictor for NODAT (31).…”

Correlation between serum levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) and atherogenic lipoproteins in patients with coronary artery disease

“…Oxidized LDL is also highly atherogenic and elevated levels of oxidized LDL recognized as a risk factor for ASCVD [ 11 , 39 ]. Oxidized LDL levels have been reported to be positively correlated with PCSK9 concentration [ 40 ]. Consistent with this finding, we observed a positive correlation between serum levels of PCSK9 and oxidized LDL.…”

Endothelial Progenitor Cells Dysfunction in Diabetes Mellitus

“…Several mechanisms are involved in the attenuation of EPCs functionality by mentioned above approaches, i.e. increase of NO production via enhancing phosphorylated-AMP-activated protein kinase and phosphorylated-eNOS, down-regulation of high mobility group box-1 and AkT / STAT signaling leading to oxidative stress suppression, attenuation of DNA / histone methylation, inhibition of progenitor cells' apoptosis and NETosis through suppression of proprotein convertase subtilisin/kexin type 9 and Dll4/Notch signaling pathway [76][77][78]. Subsequently, improving function of EPCs in DM appears to be under control and the prevention of CV complication development could be associated with restoring of EPCs-dependent repair mechanisms.…”