Apolipoprotein (a)/Lipoprotein(a)-Induced Oxidative-Inflammatory α7-nAChR/p38 MAPK/IL-6/RhoA-GTP Signaling Axis and M1 Macrophage Polarization Modulate Inflammation-Associated Development of Coronary Artery Spasm. (19th January 2022)

• Record Type: Journal Article
• Authors: Lin, Yen-Kuang; Yeh, Chi-Tai; Kuo, Kuang-Tai; Fong, Iat-Hang; Yadav, Vijesh Kumar; Kounis, Nicholas G.; Hu, Patrick; Hung, Ming-Yow
• Other Names: Cheng Xiang Academic Editor.
• Is Part Of: Oxidative medicine and cellular longevity. Volume 2022(2022)
• Publication Date: 2022-01-19
• Subjects: Oxidative stress -- Periodicals; Cells -- Aging -- Periodicals; Cells -- Aging; Oxidative stress; Oxidative Stress -- Periodicals; Cell Aging -- Periodicals; Periodicals; 611.0181
• DOI: 10.1155/2022/9964689
• Languages: English
• ISSNs: 1942-0900

Abstract

Abstract : Objective . Apolipoprotein (a)/lipoprotein(a) (Lp(a)), a major carrier of oxidized phospholipids, and α 7-nicotinic acetylcholine receptor ( α 7-nAChR) may play an important role in the development of coronary artery spasm (CAS). In CAS, the association between Lp(a) and the α 7-nAChR-modulated inflammatory macrophage polarization and activation and smooth muscle cell dysfunction remains unknown. Methods . We investigated the relevance of Lp(a)/ α 7-nAChR signaling in patient monocyte-derived macrophages and human coronary artery smooth muscle cells (HCASMCs) using expression profile correlation analyses, fluorescence-assisted cell sorting flow cytometry, immunoblotting, quantitative real-time polymerase chain reaction, and clinicopathological analyses. Results . There are increased serum Lp(a) levels (3.98-fold, p = 0.011 ) and macrophage population (3.30-fold, p = 0.013 ) in patients with CAS compared with patients without CAS. Serum Lp(a) level was positively correlated with high-sensitivity C-reactive protein (r 2 = 0.48, p < 0.01 ), IL-6 (r 2 = 0.38, p = 0.03 ), and α 7-nAChR (r 2 = 0.45, p < 0.01 ) in patients with CAS, but not in patients without CAS. Compared with untreated or low-density lipoprotein- (LDL-) treated macrophages, Lp(a)-treated macrophages exhibited markedly enhanced α 7-nAChR mRNA expression (p < 0.01 ) and activity (p < 0.01 ), in vitro and ex vivo . Lp(a) but not LDL preferentially induced CD80+ macrophage (M1) polarization and reduced the inducible nitric oxide synthase expression and the subsequent NO production. While shRNA-mediated loss of α 7-nAChR function reduced the Lp(a)-induced CD80+ macrophage pool, both shRNA and anti-IL-6 receptor tocilizumab suppressed Lp(a)-upregulated α 7-nAChR, p-p38 MAPK, IL-6, and RhoA-GTP protein expression levels in cultures of patient monocyte-derived macrophages and HCASMCs. Conclusions . Elevated Lp(a) levels upregulate α 7-nAChR/IL-6/p38 MAPK signaling in macrophages of CAS patients and HCASMC, suggesting that Lp(a)-triggered inflammation mediates CAS through α 7-nAChR/p38 MAPK/IL-6/RhoA-GTP signaling induction, macrophage M1 polarization, and HCASMC activation.