The role of PCSK9 on monocyte recruitment, cytokine synthesis and extramedullary hematopoiesis in acute myocardial infarction.

• Applicant: Dr. Jana Grune
• Subject Area: Cardiology, Angiology ; Nutritional Sciences
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 399790507

Elevated levels of Proprotein convertase subtilin-kexin 9 (PCSK9) induce deleterious cardiovascular effects, like an increase of circulating low-density lipoportein-cholesterol (LDL-C). Moreover, PCSK9 serum concentrations were shown to be upregulated directly after acute myocardial infarction (MI), indicating a role for PCSK9 during the acute period of ischemic myocardial injury. My own in vitro data revealed that PCSK9 regulates the chemotactic relevant peptide CCR2 (C-C motif chemokine receptor 2) on monocytes in a LDL-C/LDL-receptor (LDL-R) dependent manner. Newly made monocytes rely on CCR2 for their departure from the bone marrow and recruitment to the infarct. Previously, the Nahrendorf lab reported that shortly after MI hematopoietic stem and progenitor cells (HSPCs) are released from the bone marrow niche into the circulation in a CCR2 dependent manner, subsequently seeding the spleen and yielding a sustained boost in monocyte production. These data suggest a potential role for PCSK9 during acute MI, by regulating the chemokine receptor CCR2. I hypothesize that modulation of PCSK9 (in transgenic mouse models) contributes to the cardiac outcome and infarct healing after acute MI. I further hypothesize that elevated PCSK9 levels during MI lead to increased levels of plasma LDL-C and subsequent upregulation of CCR2. This will most likely stimulate splenic hematopoiesis and monocyte recruitment to the infarct, since CCR2 is necessary for monocyte infiltration. Vice versa, PCSK9 paucity should prevent cardiac monocyte recruitment, as the cells rely on the chemokine receptor for migration. Testing this hypothesis is of great clinical relevance, because anti-PCSK9 therapy has recently been granted FDA approval for patients with hypercholesterolemia. Arising evidence suggests that PCSK9 inhibitors reduce the prevalence of cardiovascular events like acute MI, pointing towards considerable adverse effects of PCSK9. However, some patients may develop acute MI despite anti-PCSK9 therapy. Therefore, further understanding of PCSK9’s molecular action on monocyte recruitment, cytokine synthesis and extramedullary hematopoiesis in acute MI is urgently needed.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Matthias Nahrendorf