Dataset Information

Integrative Proteomics and Lipidomics Analysis of Post-Myocardial Infarction Patients Treated With PCSK9 Antibodies and Statins

ABSTRACT: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a potent cholesterol-lowering strategy. This study examined effects of statins and PCSK9 monoclonal antibodies (mAbs) beyond low-density lipoprotein cholesterol reduction, which are not fully defined. To complement in vivo plasma proteomic data, we used HepG2 human hepatoma cells stably expressing apolipoprotein(a) (LPA). Cells were exposed to escalating doses of atorvastatin for ten days, followed by collection of conditioned media and cell lysates for quantitative mass spectrometric analysis. Proteomic profiling of cell lysates revealed a dose-dependent effect on HMG-CoA reductase and other enzymes within the mevalonate pathway. Analysis of conditioned media demonstrated a strong, dose-dependent induction of procollagen C-endopeptidase enhancer 1 (PCOLCE) and a modest increase in secreted LPA. These findings corroborate clinical observations that statin therapy can modestly elevate circulating lipoprotein(a) [Lp(a)] and is associated with increased plasma PCOLCE levels. The HepG2 data provide evidence for a predominant hepatic origin of this PCOLCE response, representing a novel mechanistic insight into statin-associated proteomic changes.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Culture Fluid, Cell Lysate, Hepg2 Cell

SUBMITTER: XIAOKE YIN

LAB HEAD: Prof Manuel Mayr MD PhD

PROVIDER: PXD069776 | Pride | 2026-04-27

REPOSITORIES: Pride

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Integrative Proteomic and Lipidomic Analysis of Patients With Acute Myocardial Infarction Treated With PCSK9 Antibodies and Statins.

Schmidt Lukas E LE Burnap Sean A SA Singh Bhawana B Takov Kaloyan K Losdat Sylvain S Schrutka Lore L Galli Lukas L Theofilatos Konstantinos K Otto Georg W GW Hengstenberg Christian C Tzoulaki Ioanna I Lang Irene M IM Koskinas Konstantinos C KC Speidl Walter S WS Räber Lorenz L Mayr Manuel M

Circulation. Genomic and precision medicine 20260210 2

<h4>Background</h4>PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition is a potent cholesterol-lowering strategy. This study examined the effects of PCSK9 monoclonal antibodies (mAbs) and high-intensity statins beyond low-density lipoprotein cholesterol reduction, which are not fully defined, particularly in patients with acute myocardial infarction (MI).<h4>Methods</h4>Proteomic and lipidomic analyses were conducted on plasma from 265 patients with acute MI from the PACMAN-AMI (Eff ...[more]

PMID: 41664920

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Project description:Brown adipose tissue (BAT) is a thermogenic organ that dissipates stored energy as heat to maintain body temperature in infants and small mammals. This process may also provide protection from development of diet-induced obesity. We found that the bioactive lipid mediator lysophosphatidic acid (LPA) markedly decreases differentiation of cultured primary brown adipocyte precursors, while potent selective inhibitors of the LPA-generating enzyme autotaxin (ATX) promote differentiation. Transgenic mice overexpressing ATX exhibited reduced expression of BAT-related genes in peripheral white adipose tissue and accumulated significantly more fat than wild-type controls when fed a high fat diet. Our results indicate that ATX and its product LPA are physiologically relevant negative regulators of brown fat adipogenesis and suggest that a decrease in peripheral brown adipose tissue results in increased susceptibility to diet-induced obesity in mice. Primary BAT cell cultures were established as previously reported with some minor modifications (Cannon B., 2001; NÃ©chad M., 1983). Four- to 6-week-old mice were euthanized under aseptic conditions and interscapular BAT (IBAT) dissected, finely minced in digestion buffer containing 123 mM NaCl, 5mM HCl, 1.3 mM CaCl2, 5mM glucose, 1.5% (w/v) crude bovine serum albumin fraction V, 100 mM HEPES, 0.2% collagenase type II (Sigma-Aldrich Corp., St. Louis, MO), pH 7.4, and digested in 10 ml of the same buffer for 30 min at 37Â°C. The supernatant obtained was then filtered using a 250 Âµm nylon mesh and kept in ice for 15 minutes to allow fat droplets and mature cells to float. The resulting infranatant was filtered through a 30 Âµm nylon mesh to enrich the fraction with precursor cells and centrifuged at 700g for 10 min. The pellet obtained was washed once in warm DMEM and resuspended in DMEM medium containing 10% newborn calf serum, 10 mM HEPES, 4mM glutamine, 25 Âµg/ml sodium ascorbate (Sigma-Aldrich Corp., St. Louis, MO)., 100U/ml penicillin and 100mg/ml streptomycin. Cells were seeded onto 35mm dish plates. Insulin treatment was started on day 1 at 50 nM and the concentration increased to 100 nM at day 5 and 200 nM at day 7. Differentiated/confluent cells were collected for biochemical analysis (~day 9). To identify genes regulated by ATX and LPA signaling, 9 DIV primary BAT cultures were treated with the vehicle (DMSO), specific ATX inhibitor HA155 (2.5ÂµM), or LPA (1-Oleoly-LPA, 5ÂµM) (Avanti Polar Lipids, AL, USA) during differentiation. Treatment of the BAT cultures did not affect confluence or markers of proliferation. RNA was extracted from three cultures per condition using TRIzol reagent (Invitrogen, Carlsbad, CA) as described previously (Blalock EM., 2003).

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