Abstract
Human atherosclerotic plaque contains smooth muscle cells (SMCs) negative for the contractile phenotype (α-smooth muscle actin) but positive for proprotein convertase subtilisin/kexin type 9 (PCSK9). Thus, we generated rat SMCs which overexpressed human PCSK9 (SMCsPCSK9) with the aim of investigating the role of PCSK9 in the phenotype of SMCs. PCSK9 overexpression in SMCsPCSK9 led to a significant downregulation of the low-density lipoprotein receptor (Ldlr) as well as transgelin (Sm22α), a marker of the contractile phenotype. The cell proliferation rate of SMCsPCSK9 was significantly faster than that of the control SMCs (SMCspuro). Interestingly, overexpression of PCSK9 did not impact the migratory capacity of SMCs in response to 10% FCS, as determined by Boyden’s chamber assay. Expression and activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) was significantly increased in the presence of PCSK9, both in SMCPCSK9 and after treatment with recombinant PCSK9. The transcriptional activity of sterol regulatory element-binding protein (SREBP) was also increased in the presence of PSCK9, suggesting a direct role of PCSK9 in the control of SRE-responsive genes, like HMGCR. We also observed that cholesterol biosynthesis is elevated in SMCPCSK9, potentially explaining the increased proliferation observed in these cells. Finally, concentration-dependent experiments with simvastatin demonstrated that SMCsPCSK9 were partially resistant to the antiproliferative and antimigratory effect of this drug. Taken together, these data further support a direct role of PCSK9 in proliferation, migration, and phenotypic changes in SMCs—pivotal features of atherosclerotic plaque development. We also provide new evidence on the role of PCSK9 in the pharmacological response to statins—gold standard lipid-lowering drugs with pleiotropic action.
Highlights
Clinical studies, together with in vivo and in vitro experiments, established the direct correlation between cholesterol levels, atherosclerosis, and acute coronary syndrome (ACS) [1]
Pcsk9−/− mice, and by retroviral overexpression, we demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates both Smooth Muscle Cells (SMCs) proliferation and migration—as well as their switch from a contractile to a synthetic phenotype—in a model of arterial injury [7]
The induction of PCSK9 by statins can certainly be ascribed to the activation of the sterol regulatory element-binding protein (SREBP) pathway [3,4], we previously reported a relevant role of the geranylgeranylated protein Rac1 on the regulation of PCSK9 transcription, suggesting that isoprenoid regulation might directly contribute to the statin-induced
Summary
Together with in vivo and in vitro experiments, established the direct correlation between cholesterol levels, atherosclerosis, and acute coronary syndrome (ACS) [1]. Therapies which aim to reduce low-density lipoprotein cholesterol (LDL-C), such as statins, are currently used for the treatment and prevention of ACS. Cells respond to the decreased amount of intracellular cholesterol by activating the sterol regulatory elementbinding proteins (SREBPs). These transcription factors undergo proteolytic activation resulting in the induction of LDL receptors (LDLR) and the consequent increased uptake of circulating LDL particles. SREBP activation, leads to upregulation of HMG-CoA reductase and proprotein convertase subtilisin/kexin type 9 (PCSK9). Previous studies showed that statins significantly induce PCSK9, at both mRNA and protein levels [3,4], potentially limiting the hypocholesterolemic and protective action of statins. Upregulation of PCSK9 results in reduced LDL-C uptake by hepatocytes, thereby increasing circulating
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