Abstract 13607: The Lipoprotein(a)-Induced Soluble CD36/Interleukin-6/RAS Homolog Family Member A-GTP Signaling Axis Promotes M1 Macrophage Polarization in Coronary Artery Spasm
Ming-Yow Hung, Chi-tai Yeh, Vijesh Kumar Yadav, Iat-Hang Fong- Physiology (medical)
- Cardiology and Cardiovascular Medicine
Background: We previously demonstrated that lipoprotein(a) (Lp(a)) mediated coronary artery spasm (CAS) through α7-nAChR/p38 MAPK/IL-6/RhoA-GTP signaling stimulation, macrophage M1 polarization and activation of human coronary artery smooth muscle cells (HCASMCs). While CD36, as a scavenger receptor for oxidized low-density lipoprotein, was correlated with coronary vasoconstriction in an in-vivo study, whether Lp(a) effects are related to soluble CD36 (sCD36) dependent/IL-6/RhoA-GTP inflammatory signalling remain unknown.
Methods: In patient monocyte-derived macrophages (PMDMs) and HCASMCs the relevance of Lp(a)/sCD36/IL-6/RhoA-GTP signaling axis were investigated through computational biology and experimental approaches.
Results: Plasma sCD36 levels in 25 CAS patients were significantly higher than that in 10 controls (p < 0.01). Serum Lp(a) level was positively correlated with sCD36 (r 2 =0.41, p < 0.01) in patients with CAS rather than without CAS. The RNA-sequencing revealed a significant and strong co-overexpression between the CD36 and RhoA in PMDMs and HCASMCs. Compared with untreated or low-density lipoprotein (LDL)-treated macrophages, Lp(a)-treated macrophages exhibited markedly enhanced CD36 mRNA expression (p < 0.01) and activity (p <0.01), in vitro and ex vivo . Lp(a), but not LDL, preferentially stimulated CD80+ macrophage (M1) polarization. While shRNA- mediated or Amentoflavone-, a natural CD36 suppressor, mediated functional loss of CD36 lowered Lp(a)-induced CD80+ macrophage pool, shCD36 and Overexpressed-CD-CD36 suppressed and activated Lp(a)-upregulated sCD36, TNF-α, NFκB, IL-6 and RhoA-GTP protein expression levels, respectively, in HCASMCs.
Conclusion: Lp(a) stimulated sCD36/IL-6/RhoA-GTP signaling in macrophages from CAS patients and HCASMCs, suggesting the contribution of Lp(a)-induced sCD36/IL-6/RhoA-GTP signaling, macrophage M1 polarization, and inflammation of HCASMCs in CAS development.