Introduction: Priming of human macrophages with Bacillus Calmette-Guerin vaccine (BCG) or oxidized low-density lipoprotein (oxLDL) induces a long term pro-inflammatory memory, an emerging new concept called trained innate immunity. Here we report that oxLDL or BCG priming activates corresponding mechanisms in Vascular smooth muscle cells (SMCs), leading to a sustained pro-inflammatory phenotype.
Methods: Human coronary smooth muscle cells were primed with oxLDL or BCG for 24h. After a resting time of 4 to 7 days cells were restimulated with either PAM3cys4, LPS or TNFα and cytokine production or mRNA expression were measured. Then mechanisms of monocyte trained innate immunity were analyzed in smooth muscle cells, including receptors, intracellular pathways as well as metabolic and epigenetic reprogramming
Results: Priming with oxLDL or BCG lead to a significantly increased production of IL-6, IL-8 and MCP-1 following restimulation. OxLDL priming had little effect on the expression of macrophage or SMC marker genes. Proinflammatory priming of smooth muscle cells induced mTOR-HIF1α-signaling and could be blocked by mTOR-, TLR2- and TLR4-inhibition. Finally, metabolic and epigenetic mechanisms of trained innate immunity in monocytes could be replicated in smooth muscle cells, including increased glucose consumption, lactate production, responsiveness to 6-fluoromevalonate and mevalonate treatment and inhibition of priming by the histone methyltransferase inhibitor methylthioadenosine (MTA).
Conclusion: We demonstrate that the mechanisms of trained immunity can be applied to non-immune cells of the vascular wall. Our findings warrant further research to elucidate long-term inflammatory activation of vascular SMCs.

05 - MECHANISMS OF TRAINED INNATE IMMUNITY IN OXLDL AND BCG PRIMED HUMAN CORONARY SMOOTH MUSCLE CELLS