Immune Regulation of the Liver Through the PCSK9/CD36 Pathway During Heart Transplant Rejection

Circulation, Год журнала: 2023, Номер 148(4), С. 336 - 353

Опубликована: Май 26, 2023

PCSK9 (proprotein convertase subtilisin/kexin 9), which is mainly secreted by the liver, not only a therapeutic target for hyperlipidemia and cardiovascular disease, but also has been implicated in immune regulation of infections tumors. However, role liver heart transplant rejection (HTR) underlying mechanisms remain unclear.We assessed serum expression both murine human recipients during HTR investigated effect ablation on using global knockout mice neutralizing antibody. Moreover, we performed multiorgan histological transcriptome analyses, multiomics single-cell RNA-sequencing studies HTR, as well. We further used hepatocyte-specific Pcsk9 to investigate whether regulated through PCSK9. Last, explored regulatory PCSK9/CD36 pathway phenotype function macrophages vitro vivo.Here, report that have high levels HTR. prolonged cardiac allograft survival attenuated infiltration inflammatory cells graft expansion alloreactive T spleen. Next, demonstrated was produced significantly upregulated recipient showed series signaling changes, including changes TNF-α (tumor necrosis factor α) IFN-γ (interferon γ) pathways bile acid fatty metabolism pathways. found mechanistically synergistically promoted hepatocytes transcription SREBP2 (sterol element binding protein 2). vivo indicated inhibited CD36 uptake strengthened proinflammatory phenotype, facilitated their ability promote proliferation production donor-reactive cells. protective against dependent recipient.This study reveals novel mechanism influences suggests modulation this may be potential prevent

Язык: Английский

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Targeting PCSK9 reduces cancer cell stemness and enhances antitumor immunity in head and neck cancer

iScience, Год журнала: 2023, Номер 26(6), С. 106916 - 106916

Опубликована: Май 19, 2023

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been demonstrated to play a critical role in regulating cholesterol homeostasis and T cell antitumor immunity. However, the expression, function, therapeutic value of PCSK9 head neck squamous carcinoma (HNSCC) remain largely unexplored. Here, we found that expression was upregulated HNSCC tissues, higher indicated poorer prognosis patients. We further pharmacological inhibition or siRNA downregulating suppressed stemness-like phenotype cancer cells an LDLR-dependent manner. Moreover, enhanced infiltration CD8+ reduced myeloid-derived suppressor (MDSCs) 4MOSC1 syngeneic tumor-bearing mouse model, it also effect anti-PD-1 immune checkpoint blockade (ICB) therapy. Together, these results PCSK9, traditional hypercholesterolemia target, may be novel biomarker target enhance ICB therapy HNSCC.

Язык: Английский

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MK-0616: an oral PCSK9 inhibitor for hypercholesterolemia treatment

Expert Opinion on Investigational Drugs, Год журнала: 2023, Номер 32(10), С. 873 - 878

Опубликована: Окт. 3, 2023

ABSTRACTIntroduction Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality worldwide. Lowering LDL-cholesterol, by lifestyle modification or therapeutically, reduces the risk ASCVD. Proprotein convertase subtilisin/kexin type 9 (PCSK9), protein which binds to LDL-receptor induces degradation, clinically validated target lower LDL-cholesterol. Injectable PCSK9 inhibitor therapies have demonstrated substantial reductions in LDL-cholesterol with associated decreased ASCVD events.Areas covered MK-0616 an orally bioavailable, renally excreted, macrocyclic peptide PCSK9. The article provides understanding chemistry development, pharmacokinetic pharmacodynamic characteristics insight into its clinical efficacy safety. In trials, produced dose-dependent non-HDL-cholesterol, apolipoprotein (apo) B levels. Furthermore, modestly lowered lipoprotein (a) [Lp(a)].Expert opinion potent, oral that not only able reduce apoB, but can also Lp(a). Safety tolerability studies reported date are promising. may offer advantages over injectable anti-PCSK9 terms ease dosing, patient preference cost. results from phase III trials on outcomes awaited interest.KEYWORDS: ApoBLDL-cholesterolnon-HDL-cholesterolLp(a)MK-0616PCSK9PCSK9 Declaration interestsThe authors no relevant affiliations financial involvement any organization entity interest conflict subject matter materials discussed manuscript. This includes employment, consultancies, honoraria, stock ownership options, expert testimony, grants patents received pending, royalties.Reviewer disclosuresPeer reviewers this manuscript other relationships disclose.Additional informationFundingThis paper was funded.

Язык: Английский

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Blockade of Hepatocyte PCSK9 Ameliorates Hepatic Ischemia-Reperfusion Injury by Promoting Pink1-Parkin–Mediated Mitophagy

Cellular and Molecular Gastroenterology and Hepatology, Год журнала: 2023, Номер 17(1), С. 149 - 169

Опубликована: Сен. 16, 2023

Язык: Английский

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Lowering LDL cholesterol by PCSK9 inhibition: a new era of gene silencing, RNA, and alternative therapies

Naunyn-Schmiedeberg s Archives of Pharmacology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Язык: Английский

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