Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9

Macchi, Chiara; Greco, Maria Francesca; Botta, Margherita; Sperandeo, Paola; Dongiovanni, Paola; Valenti, Luca; Cicero, Arrigo Francesco Giuseppe; Borghi, Claudio; Lupo, Maria Giovanna; Romeo, Stefano; Corsini, Alberto; Magni, Paolo; Ferri, Nicola; Ruscica, Massimiliano

doi:10.1016/j.ajpath.2020.07.016

Cited by 27 publications

(24 citation statements)

References 54 publications

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“…Vice versa, in conditions of dysfunctional visceral fat depots PCSK9 is induced by leptin and resistin through the involvement of the inflammatory pathway of STAT3. In HepG2 cells, leptin and resistin up-regulated PCSK9 gene and protein expression (Macchi et al, 2020b). However, at least in our cohort, circulating leptin, although higher in women than men, was not related to either PCSK9 or memory function.…”

Section: Discussioncontrasting

confidence: 66%

Sex-Specific Association of Endogenous PCSK9 With Memory Function in Elderly Subjects at High Cardiovascular Risk

Simeone

Vadini

Tripaldi

et al. 2021

Front. Aging Neurosci.

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Background: Growing evidence indicates that cognitive decline and cardiovascular diseases (CVDs) share common vascular risk factors. Protease proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with CV disease risk and has been also involved in neuronal differentiation.Aim: Evaluate whether in patients at high CV risk cognitive function is related to PCSK9 levels.Methods. One hundred sixty-six patients (67 female) were enrolled. A detailed neuropsychological (NP) assessment was performed. PCSK9 levels were measured with ELISA.Results: Men had significantly higher short-term memory, executive function, and praxic and mental representation skills, as reflected by Forward Digit Span (FDS) (p = 0.005), Trail Making Test-A (TMT-A) (p = 0.047), Clock Drawing Test (CDT) (0.016). Endogenous PCSK9 levels were higher in female (p = 0.005). On linear regression analysis PCSK9 predicts short term memory only in females (Beta = 0.408, p = 0.001), with an interaction between PCSK9 and gender (p = 0.004 for interaction PCSK9 by sex). The association of PCSK9 with FDS in female was partially mediated by waist circumference (mediation effect 8.5%).Conclusions: In patients at high CV risk short term memory was directly related to PCSK9 levels only in women, revealing the relevance of sex in this relationship. The association of PCSK9 with memory function may be mediated, at least in part, by waist circumference.

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Section: Discussioncontrasting

confidence: 66%

Sex-Specific Association of Endogenous PCSK9 With Memory Function in Elderly Subjects at High Cardiovascular Risk

Simeone

Vadini

Tripaldi

et al. 2021

Front. Aging Neurosci.

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“…Vice-versa, inflammatory pathways such as interferon (IFN)-γ can also increase both PCSK9 gene and protein expression [ 13 ]. In line with this, it could also be observed that the inflammatory pathways of STAT3 [ 36 ] and SOCS3 [ 37 ] induce the expression of PCSK9, clearly demonstrating that PCSK9 expression increases in an inflammatory environment. Additionally, it could be shown that PCSK9 aggravates atherosclerosis in apolipoprotein-E deficient mice [ 38 ], which was associated with an increased expression of inflammatory cytokines such as TNF-α, IL-1β, IL-10, MCP-1, and IL-8 to directly facilitate the process of inflammation.…”

Section: Discussionsupporting

confidence: 54%

PCSK9 Imperceptibly Affects Chemokine Receptor Expression In Vitro and In Vivo

Sundararaman

Peters

Nazir

et al. 2021

IJMS

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Proprotein convertase subtilin/kexin type 9 (PCSK9) is a protease secreted mainly by hepatocytes and in lesser quantities by intestines, pancreas, and vascular cells. Over the years, this protease has gained importance in the field of cardiovascular biology due to its regulatory action on the low-density lipoprotein receptor (LDLR). However, recently, it has also been shown that PCSK9 acts independent of LDLR to cause vascular inflammation and increase the severity of several cardiovascular disorders. We hypothesized that PCSK9 affects the expression of chemokine receptors, major mediators of inflammation, to influence cardiovascular health. However, using overexpression of PCSK9 in murine models in vivo and PCSK9 stimulation of myeloid and vascular cells in vitro did not reveal influences of PCSK9 on the expression of certain chemokine receptors that are known to be involved in the development and progression of atherosclerosis and vascular inflammation. Hence, we conclude that the inflammatory effects of PCSK9 are not associated with the here investigated chemokine receptors and additional research is required to elucidate which mechanisms mediate PCSK9 effects independent of LDLR.

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“…The results of this study did not demonstrate any association between PCSK9 with the majority of these biomarkers. On the other hand, a growing body of experimental evidence, as aforementioned, highlights the key role of PCSK9 in the pathogenesis of atherosclerosis by its implication in inflammation, apoptosis, oxidative stress, and endothelial damage [16,54]. Clinical observational data are conflicting regarding the role of PCSK9 as a predictive risk factor for mortality in CKD patients.…”

Section: Discussionmentioning

confidence: 99%

Association between PCSK9 Levels and Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction in a Population of Nondialysis Chronic Kidney Disease Patients

Dounousi

Tellis

Pavlakou

et al. 2021

Oxidative Medicine and Cellular Longevity

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Proprotein convertase subtilisin/kexin 9 (PCSK9) plays an important role in lipid metabolism while available literature regarding its involvement in the pathogenesis of atherosclerosis and in the expression of genes associated with apoptosis and inflammation is constantly increasing. Patients with chronic kidney disease (CKD) experience disproportionately increased cardiovascular morbidity and mortality due to dyslipidemia, accelerated atherosclerosis, inflammation, oxidative stress, and other risk factors. In the present cross-sectional study, we investigated the possible association of serum PCSK9 levels with markers of inflammation, oxidative stress, and endothelial damage in patients with CKD. Patients and Methods. Ninety-two patients with CKD stages II-ΙV (eGFR CKD-EPI 47.3 ± 25.7 ml/min/1.73 m2, mean age 66 years, 51 men) were included in the study. Plasma PCSK9 levels were correlated with comorbidities (arterial hypertension, diabetes mellitus, and history of cardiovascular disease), renal function indices (eGFR, proteinuria–UPR/24 h), lipid parameters (LDL-cholesterol, HDL-cholesterol, triglycerides, Lp(a), APO-A1, and APO-B), and soluble biomarkers of inflammation, oxidative stress, and endothelial damage (hs-CRP, fibrinogen, 8-epiPGF2a, ox-LDL, IL-6, TNF-α, sICAM-1, and sVCAM-1). Results. The mean plasma value of PCSK9 was 278.1 ng/ml. PCSK9 levels showed direct correlation with serum triglycerides ( p = 0.03 ), Lp(a) ( p = 0.01 ), and sICAM-1 levels ( p = 0.03 ). There was no significant correlation between PCSK9 levels and indices of the renal function, other lipid profile parameters, inflammatory markers, or comorbidities. Multiple regression analysis showed a significant effect of Lp(a) on PCSK9 levels, and for each unit of higher Lp(a), an increase by 3.082 is expected (95% CI: 0.935-5.228, p = 0.006 ). At the same time, patients receiving statins are expected to have on average 63.8 ng/ml higher PCSK9 values compared to patients not receiving statins (95% CI: 14.6-113.5, p = 0.012 ). Conclusion. Plasma levels of PCSK9 in nondialysis CKD patients are correlated with endothelial dysfunction and lipid metabolism parameters. Statin intake increases PCSK9 levels significantly in this patient population. PCSK9 levels are not correlated with the severity of kidney disease. Major prospective studies are necessary to investigate the role of PCSK9 in the atherosclerotic cardiovascular outcome in CKD.

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Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9

Cited by 27 publications

References 54 publications

Sex-Specific Association of Endogenous PCSK9 With Memory Function in Elderly Subjects at High Cardiovascular Risk

Sex-Specific Association of Endogenous PCSK9 With Memory Function in Elderly Subjects at High Cardiovascular Risk

PCSK9 Imperceptibly Affects Chemokine Receptor Expression In Vitro and In Vivo

Association between PCSK9 Levels and Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction in a Population of Nondialysis Chronic Kidney Disease Patients

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