Autocrine effects of PCSK9 on cardiomyocytes

Wolf, Annemarie; Kutsche, Hanna Sarah; Schreckenberg, Rolf; Weber, Martin; Li, Ling; Rohrbach, Susanne; Schulz, Rainer; Schlüter, Klaus‐Dieter

doi:10.1007/s00395-020-00824-w

Cited by 19 publications

(23 citation statements)

References 38 publications

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“…Under basal conditions, PCSK9 is expressed at very low levels in the heart ( Supplementary material online, Figure S7I ) but is induced in vivo under ischaemic conditions 32 and in vitro following incubation with oxidized LDL. 33 It has been hypothesized that PCSK9 induction immediately after ischemia/reperfusion injury might protect the heart in the acute phase by stimulating autophagic process and the removals of damaged mitochondria, 32 an effect that could became deleterious over time as might lead to increased cell deterioration and cardiomyocyte death. It is also possible that PCSK9 produced locally by epicardial adipose tissue 34 contributes to this pathophysiological change, a finding supported by the observation that the R46L variant is associated with increased epicardial fat accumulation in humans, 23 independently of obesity or diabetes.…”

Section: Discussionmentioning

confidence: 99%

PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction

Dalt

Castiglioni

Baragetti

et al. 2021

European Heart Journal

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Aims PCSK9 is secreted into the circulation, mainly by the liver, and interacts with low-density lipoprotein receptor (LDLR) homologous and non-homologous receptors, including CD36, thus favouring their intracellular degradation. As PCSK9 deficiency increases the expression of lipids and lipoprotein receptors, thus contributing to cellular lipid accumulation, we investigated whether this could affect heart metabolism and function. Methods and results Wild-type (WT), Pcsk9 KO, Liver conditional Pcsk9 KO and Pcsk9/Ldlr double KO male mice were fed for 20 weeks with a standard fat diet and then exercise resistance, muscle strength, and heart characteristics were evaluated. Pcsk9 KO presented reduced running resistance coupled to echocardiographic abnormalities suggestive of heart failure with preserved ejection fraction (HFpEF). Heart mitochondrial activity, following maximal coupled and uncoupled respiration, was reduced in Pcsk9 KO mice compared to WT mice and was coupled to major changes in cardiac metabolism together with increased expression of LDLR and CD36 and with lipid accumulation. A similar phenotype was observed in Pcsk9/Ldlr DKO, thus excluding a contribution for LDLR to cardiac impairment observed in Pcsk9 KO mice. Heart function profiling of the liver selective Pcsk9 KO model further excluded the involvement of circulating PCSK9 in the development of HFpEF, pointing to a possible role locally produced PCSK9. Concordantly, carriers of the R46L loss-of-function variant for PCSK9 presented increased left ventricular mass but similar ejection fraction compared to matched control subjects. Conclusion PCSK9 deficiency impacts cardiac lipid metabolism in an LDLR independent manner and contributes to the development of HFpEF.

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Section: Discussionmentioning

confidence: 99%

PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction

Dalt

Castiglioni

Baragetti

et al. 2021

European Heart Journal

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“…Whether PCSK9 targets intracellular proteins or acts via secretion in cardiomyocytes has been analyzed in detail. In summary, the secretion of PCSK9 by cardiomyocytes via Surf-4 is responsible for the effect of oxLDL on cardiomyocytes ( Wolf et al, 2020 ). In line with this, plasma concentration of PCSK9 is associated with heart failure ( Chandrakala et al, 2012 ).…”

Section: The Role Of Pcsk9 In Striated Musclesmentioning

confidence: 99%

Coming Back to Physiology: Extra Hepatic Functions of Proprotein Convertase Subtilisin/Kexin Type 9

2020

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Neuronal apoptosis regulated convertase-1 (NARC-1), now mostly known as proprotein convertase subtilisin/kexin type 9 (PCSK9), has received a lot of attention due to the fact that it is a key regulator of the low-density lipoprotein (LDL) receptor (LDL-R) and is therefore involved in hepatic LDL clearance. Within a few years, therapies targeting PCSK9 have reached clinical practice and they offer an additional tool to reduce blood cholesterol concentrations. However, PCSK9 is almost ubiquitously expressed in the body but has less well-understood functions and target proteins in extra hepatic tissues. As such, PCSK9 is involved in the regulation of neuronal survival and protein degradation, it affects the expression of the epithelial sodium channel (ENaC) in the kidney, it interacts with white blood cells and with cells of the vascular wall, and it modifies contractile activity of cardiomyocytes, and contributes to the regulation of cholesterol uptake in the intestine. Moreover, under stress conditions, signals from the kidney and heart can affect hepatic expression and thereby the plasma concentration of PCSK9 which then in turn can affect other target organs. Therefore, there is an intense relationship between the local (autocrine) and systemic (endocrine) effects of PCSK9. Although, PCSK9 has been recognized as a ubiquitously expressed modifier of cellular function and signaling molecules, its physiological role in different organs is not well-understood. The current review summarizes these findings.

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“…The proprotein convertase subtilisin kexin type 9 (PCSK9), identified in 2001 with its gene characterization in 2003 [ 8 ], acts as a negative regulator of LDLR by binding to LDLR and therefore increases LDL-C [ 9 ], leading to atherosclerotic coronary artery disease [ 4 ], with or without endothelial dysfunction [ 10 ]. Hypercholesterolemia can further increase PCSK9 [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Beyond its role in cholesterol homeostasis, PCSK9 is prevalent in human macrophages [ 12 ], smooth muscle cells, endothelial cells [ 13 ], and cardiomyocytes, [ 9 ] with a local effect that can regulate vascular homeostasis and atherosclerosis [ 12 ], suggesting a different role of PCSK9 in the heart. In rat cardiomyocytes, while overexpression of human PCSK9 reduces cell shortening independent of oxidized LDL, silencing of PCSK9 in cardiomyocytes attenuates oxidized LDL-dependent effects on cell shortening [ 9 ]. Moreover, oxidized LDL induces PCSK9 release from cardiomyocytes into the supernatant [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…In rat cardiomyocytes, while overexpression of human PCSK9 reduces cell shortening independent of oxidized LDL, silencing of PCSK9 in cardiomyocytes attenuates oxidized LDL-dependent effects on cell shortening [ 9 ]. Moreover, oxidized LDL induces PCSK9 release from cardiomyocytes into the supernatant [ 9 ]. Hence, PCSK9 acts in a direct, autocrine way on cardiomyocytes and impairs their function [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Pterostilbene Increases LDL Metabolism in HL-1 Cardiomyocytes by Modulating the PCSK9/HNF1α/SREBP2/LDLR Signaling Cascade, Upregulating Epigenetic hsa-miR-335 and hsa-miR-6825, and LDL Receptor Expression

et al. 2021

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) can promote the degradation of low-density lipoprotein (LDL) receptor (LDLR), leading to hypercholesterolemia and myocardial dysfunction. The intracellular regulatory mechanism by which the natural polyphenol pterostilbene modulates the PCSK9/LDLR signaling pathway in cardiomyocytes has not been evaluated. We conducted Western blotting, flow cytometry, immunofluorescence staining, and mean fluorescence intensity analyses of pterostilbene-treated mouse HL-1 cardiomyocytes. Pterostilbene did not alter cardiomyocyte viability. Compared to the control group, treatment with both 2.5 and 5 μM pterostilbene significantly increased the LDLR protein expression accompanied by increased uptake of LDL. The expression of the mature PCSK9 was significantly suppressed at the protein and mRNA level by the treatment with both 2.5 and 5 μM pterostilbene, respectively, compared to the control. Furthermore, 2.5 and 5 μM pterostilbene treatment resulted in a significant reduction in the protein hepatic nuclear factor 1α (HNF1α)/histone deacetylase 2 (HDAC2) ratio and sterol regulatory element-binding protein-2 (SREBP2)/HDAC2 ratio. The expression of both hypoxia-inducible factor-1 α (HIF1α) and nuclear factor erythroid 2-related factor 2 (Nrf2) at the protein level was also suppressed. Pterostilbene as compared to short hairpin RNA against SREBP2 induced a higher protein expression of LDLR and lower nuclear accumulation of HNF1α and SREBP2. In addition, pterostilbene reduced PCSK9/SREBP2 interaction and mRNA expression by increasing the expression of hsa-miR-335 and hsa-miR-6825, which, in turn, increased LDLR mRNA expression. In cardiomyocytes, pterostilbene dose-dependently decreases and increases the protein and mRNA expression of PCSK9 and LDLR, respectively, by suppressing four transcription factors, HNF1α, SREBP2, HIF1α, and Nrf2, and enhancing the expression of hsa-miR-335 and hsa-miR-6825, which suppress PCSK9/SREBP2 interaction.

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Autocrine effects of PCSK9 on cardiomyocytes

Cited by 19 publications

References 38 publications

PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction

PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction

Coming Back to Physiology: Extra Hepatic Functions of Proprotein Convertase Subtilisin/Kexin Type 9

Pterostilbene Increases LDL Metabolism in HL-1 Cardiomyocytes by Modulating the PCSK9/HNF1α/SREBP2/LDLR Signaling Cascade, Upregulating Epigenetic hsa-miR-335 and hsa-miR-6825, and LDL Receptor Expression

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