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Targeting the High-Density Lipoprotein Proteome for the Treatment of Post-Acute Sequelae of SARS-CoV-2

https://doi.org/10.1007/s00392-025-02625-4

Elisabeth Schieffer (Marburg)1, K. Grote (Marburg)1, A.-C. Schäfer (Marburg)1, M. Soufi (Marburg)1, V. Ruppert (Marburg)1, U. Linne (Marburg)1, A. Bhagwat (Marburg)1, W. Szymanski (Marburg)1, J. Graumann (Marburg)1, Y. Gercke (Marburg)1, S. Aldudak (Marburg)1, D. Hilfiker-Kleiner (Hannover)2, B. Schieffer (Marburg)1

1Philipps Universität Marburg Marburg, Deutschland; 2Medizinische Hochschule Hannover Hannover, Deutschland

 

Background and Aims: We investigated the high-density lipoprotein (HDL) proteome in a case series of 16 patients who suffered from persistent symptoms (post-acute sequelae) after serologically confirmed SARS-CoV-2 infection (post-COVID-19 syndrome, PCS, n = 8) or following SARS-CoV-2 vaccination (PVS, n = 8) before and after treatment with HMG-Co-A reductase inhibitor (statin) plus angiotensin II type 1 receptor blocker (ARBs) for 6 weeks. Asymptomatic subjects with corresponding serological findings served as healthy controls (n = 8/8).

Methods and Results: HDL was isolated using dextran sulfate precipitation and the HDL proteome of all study participants was analyzed quantitatively by mass spectrometry. Clinical symptoms were assessed using questionnaires before and after therapy. The inflammatory potential of the patients' HDL proteome was addressed in human endothelial cells. The HDL proteome of patients with PCS and PVS showed no significant differences; however, compared to controls, the HDL from PVS/PCS patients displayed significant alterations involving hemoglobin, cytoskeletal proteins (MYL6, TLN1, PARVB, TPM4, FLNA), and amyloid precursor protein. Gene Ontology Biological Process (GOBP) enrichment analysis identified hemostasis, peptidase, and lipoprotein regulation pathways to be involved. Treatment of PVS/PCS patients with statin plus ARB improved clinical symptoms. After therapy, three proteins were significantly increased (FAM3C, AT6AP2, ADAM10; FDR < 0.05) in the HDL proteome from patients with PVS/PCS. Exposure of human endothelial cells with the HDL proteome from treated PVS/PCS patients revealed reduced inflammatory cytokine and adhesion molecule expression.

Conclusions: HDL proteome analysis from PVS/PCS patients enables a deeper insight into the underlying disease mechanisms, indicating significant involvement in metabolic and signaling disturbances. Treatment with statin plus ARB improved clinical symptoms and reduced the inflammatory potential of the HDL proteome.

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