PCSK9 regulates the chemokine receptor CCR2 on monocytes

Grune, Jana; Meýborg, Heike; Bezhaeva, Taisiya; Kappert, Kai; Hillmeister, Philipp; Kintscher, Ulrich; Pieske, Burkert; Stawowy, Philipp

doi:10.1016/j.bbrc.2017.02.085

Cited by 40 publications

(41 citation statements)

References 37 publications

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“…The pro-inflammatory effect of PCSK9 has been shown in different experimental models [27][28][29]. The inhibitory effect of PCSK9 on vascular calcification was also suggested in several basic experiments [30,31]. In addition, clinical evidence supported a linkage between PCSK9 and chemokine and vascular calcification in previous studies [24,32].…”

Section: Discussionmentioning

confidence: 80%

Circulating PCSK9 Level and Risk of Cardiovascular Events and Death in Hemodialysis Patients

Hwang

Kim

et al. 2020

JCM

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for the prevention of cardiovascular (CV) events. However, the clinical significance of circulating PCSK9 is unclear in hemodialysis (HD) patients. A total of 353 HD patients were prospectively enrolled from June 2016 to August 2019 in a K-cohort. Plasma PCSK9 level was measured at the time of study enrollment. The primary endpoint was defined as a composite of CV event and death. Plasma PCSK9 level was positively correlated with total cholesterol level in patients with statin treatment. Multivariate linear regression analysis revealed that baseline serum glucose, albumin, total cholesterol, and statin treatment were independent determinants of circulating PCSK9 levels. Cumulative rates of composite and CV events were significantly higher in patients with tertile 3 PCSK9 (p = 0.017 and p = 0.010, respectively). In multivariate Cox-regression analysis, PCSK9 tertile 3 was associated with a 1.97-fold risk of composite events (95% CI, 1.13–3.45), and it was associated with a 2.31-fold risk of CV events (95% CI, 1.17–4.59). In conclusion, a higher circulating PCSK9 level was independently associated with incident CV events and death in HD patients. These results suggest the importance of future studies regarding the effect of PCSK9 inhibition.

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Section: Discussionmentioning

confidence: 80%

Circulating PCSK9 Level and Risk of Cardiovascular Events and Death in Hemodialysis Patients

Hwang

Kim

et al. 2020

JCM

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“…Moreover, PCSK9 levels related only modestly to LDL-c in this group. A fascinating literature has emerged suggesting that PCSK9 secreted by arterial wall endothelial and smooth muscle cells [ 25 ] may promote inflammation and atherogenesis in situ through the following mechanisms: (1) upregulating endothelial expression of vascular cell adhesion molecule-1 (VCAM-1), thus facilitating monocytes-to-endothelial adhesion [ 25 ]; (2) promoting a pro-inflammatory response by local macrophages [ 8 , 26 , 27 ]; and (3) inhibiting macrophage expression of ATP-binding cassette subfamily A member 1 (ABCA1), thus impeding reverse cholesterol transport and engendering foam cell formation [ 28 ]. Indeed, in murine models, PCSK9 has been shown to accumulate in the arterial wall, influencing atheroma size and composition, independent of LDL-c levels [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Proprotein Convertase Subtilisin/Kexin 9 Levels in Relation to Systemic Immune Activation and Subclinical Coronary Plaque in HIV

Zanni

Stone

Toribio

et al. 2017

Open Forum Infectious Diseases

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BackgroundProprotein convertase subtilisin/kexin 9 (PCSK9) is known to mediate homeostasis of low-density lipoprotein cholesterol (LDL-c), but it may also participate in immune reactivity and atherogenesis.MethodsWe compared circulating PCSK9 levels among asymptomatic individuals with and without HIV. Further, within each group, we assessed the relationship between PCSK9 levels, traditional cardiovascular disease risk factors, immune activation, and subclinical coronary atherosclerotic plaque.ResultsPCSK9 levels were higher among HIV-infected (n = 149) vs matched non-HIV-infected subjects (n = 69; 332 [272, 412] ng/mL vs 304 [257, 375] ng/mL; P = .047). Among HIV-infected subjects, significant albeit modest positive associations were noted between PCSK9 levels and markers of systemic monocyte activation including sCD14 (rho = 0.22; P = .009) and sCD163 (rho = 0.23; P = .006). In this group, PCSK9 levels related weakly to LDL-c (rho = 0.16; P = .05) and also to Framingham Point Score but did not relate to subclinical coronary atherosclerotic plaque parameters.ConclusionsAmong HIV-infected individuals, circulating PCSK9 levels are elevated and related to systemic markers of monocyte activation but not to coronary plaque parameters. Additional studies are needed to determine the effects of PCSK9 on immune activation and atherogenesis in HIV and to assess whether PCSK9 inhibition reduces immune activation and coronary atherosclerotic plaque burden.Clinical Trial RegistrationNCT00455793.

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“…While activation of plasma membrane-bound LRP-1 depresses nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling, extracellular LRP-1 activates stress activated kinases like p38 MAP kinase [119]. While the activation of LRP-1 attenuates LPS-driven inflammation, LPS itself increases the expression of PCSK9 and, therefore, decreases the hepatic expression of LDLR [51, 68]. This leads to increased plasma LDL-C and indirectly oxLDL, as well.…”

Section: Pcsk9 Effects Distinct From Hepatic Ldlr Regulationmentioning

confidence: 99%

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

et al. 2017

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Ischemic heart disease is the main cause of death worldwide and is accelerated by increased levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL-C through its ability to induce degradation of the LDL receptor (LDLR) in the lysosome of hepatocytes. Only in the last few years, a number of breakthroughs in the understanding of PCSK9 biology have been reported illustrating how PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Two humanized antibodies directed against the LDLR-binding site in PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics are climbing up the phases of clinical trials. The first outcome data of the PCSK9 inhibitor evolocumab reported a significant reduction in the composite endpoint (cardiovascular death, myocardial infarction, or stroke) and further outcome data are awaited. Meanwhile, it became evident that PCSK9 has (patho)physiological roles in several cardiovascular cells. In this review, we summarize and discuss the recent biological and clinical data on PCSK9, the regulation of PCSK9, its extra-hepatic activities focusing on cardiovascular cells, molecular concepts to target PCSK9, and finally briefly summarize the data of recent clinical studies.

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PCSK9 regulates the chemokine receptor CCR2 on monocytes

Cited by 40 publications

References 37 publications

Circulating PCSK9 Level and Risk of Cardiovascular Events and Death in Hemodialysis Patients

Circulating PCSK9 Level and Risk of Cardiovascular Events and Death in Hemodialysis Patients

Proprotein Convertase Subtilisin/Kexin 9 Levels in Relation to Systemic Immune Activation and Subclinical Coronary Plaque in HIV

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease

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