Clin Res Cardiol (2022).

Pcsk9-targeting in healing of experimental myocardial infarction, a double-edged sword
S. Rauterberg1, J. Hein1, P. Schrepf1, D. Wolf1, P. Stachon1, C. Bode1, I. Hilgendorf1
1Klinik für Kardiologie und Angiologie I, Universitäts-Herzzentrum Freiburg - Bad Krozingen GmbH, Freiburg im Breisgau;
Proproteinconvertase Subtilisin/ Kexin 9 (PCSK9) is a secreted serine protease known best for its LDL-Receptor degrading function. Therapeutically human monoclonal antibodies directed against PCSK9 are used to lower cholesterol levels via LDLR recycling thereby protecting from cardiovascular events. However, whether and how PCSK9 itself affects cardiac remodeling post myocardial infarction (MI) in a cholesterol-independent manner remains elusive. Both protective and detrimental effects are conceivable as PCSK9 may target different cardiac cell types, lipid and scavenger receptors.
Results and Methods:
Pcsk9-/- mice, as well as C57Bl/6J wildtype mice receiving anti-PCSK9 antibody Alirocumab underwent permanent ligation of the LAD.
Knockout mice showed increased survival post MI compared to PCSK9+/+ mice, to our surprise, an effect not reproducible with antibody treatment and even hinting at adverse outcomes. Antibody treatment resulted in the accumulation of total PCSK9 in blood and heart tissue. Cell culture experiments confirmed that antibody-bound PCSK9, although no longer capable of degrading LDL receptors in hepatocytes, still exerted pro-inflammatory effects in macrophages in a dosedependent manner.
Conclusions: Pcsk9 deficiency improves post-myocardial infarction healing in mice, whereas PCSK9-blockade, by accumulating PCSK9 in the infarcted heart, may even act detrimentally due to an increased inflammatory response.