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

Abstract

Objective. Apolipoprotein (a)/lipoprotein(a) (Lp(a)), a major carrier of oxidized phospholipids, and α7-nicotinic acetylcholine receptor (α7-nAChR) may play an important role in the development of coronary artery spasm (CAS). In CAS, the association between Lp(a) and the α7-nAChR-modulated inflammatory macrophage polarization and activation and smooth muscle cell dysfunction remains unknown. Methods. We investigated the relevance of Lp(a)/α7-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 α7-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 α7-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 α7-nAChR function reduced the Lp(a)-induced CD80+ macrophage pool, both shRNA and anti-IL-6 receptor tocilizumab suppressed Lp(a)-upregulated α7-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 α7-nAChR/IL-6/p38 MAPK signaling in macrophages of CAS patients and HCASMC, suggesting that Lp(a)-triggered inflammation mediates CAS through α7-nAChR/p38 MAPK/IL-6/RhoA-GTP signaling induction, macrophage M1 polarization, and HCASMC activation.

Non-linear Associations Between Visceral Adiposity Index and Cardiovascular and Cerebrovascular Diseases: Results From the NHANES (1999–2018)

“…Further, the VAI was associated with chronic inflammation and insulin resistance, due to increases in free fatty acids, interleukin-6, tumor necrosis factor-α, and decreased adiponectin production, related to VAT (23). Inflammatory cytokines and reactive oxygen species lead to decreased nitric oxide concentrations, which are associated with a higher risk of arterial stiffness (24)(25)(26)(27). Additionally, large quantities of fatty acids, due to accumulative visceral adiposity and chronic inflammation, can promote the likelihood of insulin resistance, which is associated with atherosclerosis (28)(29)(30)(31).…”

Luteolin suppresses the growth of colon cancer cells by inhibiting the IL-6/STAT3 signaling pathway

“…Cellular immune metabolism may be an important factor in the regulation of macrophage polarization (36). It has also been reported that M1 polarized macrophages promote inflammation by producing the pro-inflammatory factor, IL-6 (37,38). Immune cells present in the inflammatory tumor microenvironment may be key to promoting cancer development (39,40).…”

Variant Angina is Associated with Myocarditis

“…20 Increased cytokine levels from neutrophils and macrophages, such as IL-6, can enhance coronary contractions by activating Rho-associated kinase. 21,22 In addition, IL-1 induces the synthesis of inflammatory mediators, prostacyclin, and platelet-activating factor, which directly induce CAS. 6,23 Hypersensitivity has been recognized to be related to VSA, which is referred to as Kounis syndrome.…”