Macrophage polarization markers in subcutaneous, pericardial, and epicardial adipose tissue are altered in patients with coronary heart disease

Abstract

BackgroundEpicardial and pericardial adipose tissue (EAT and PAT) surround and protect the heart, with EAT directly sharing the microcirculation with the myocardium, possibly presenting a distinct macrophage phenotype that might affect the inflammatory environment in coronary heart disease (CHD). This study aims to investigate the expression of genes in different AT compartments driving the polarization of AT macrophages toward an anti-inflammatory (L-Galectin 9; CD206) or pro-inflammatory (NOS2) phenotype.MethodsEAT, PAT, and subcutaneous (SAT) biopsies were collected from 52 CHD patients undergoing coronary artery bypass grafting, and from 22 CTRLs undergoing aortic valve replacement. L-Galectin9 (L-Gal9), CD206, and NOS2 AT gene expression and circulating levels were analyzed through RT-PCR and ELISA, respectively.ResultsL-Gal9, CD206, and NOS2 gene expression was similar in all AT compartments in CHD and CTRLs, as were also L-Gal9 and CD206 circulating levels, while NOS2 serum levels were higher in CHD (p = 0.012 vs. CTRLs). In CTRLs, NOS2 expression was lower in EAT vs. SAT (p = 0.007), while in CHD patients CD206 expression was lower in both SAT and EAT as compared to PAT (p = 0.003, p = 0.006, respectively), suggestive of a possible macrophage reprogramming toward a pro-inflammatory phenotype in EAT. In CHD patients, NOS2 expression in SAT correlated to that in PAT and EAT (p = 0.007, both), CD206 expression correlated positively to L-Gal9 (p < 0.001) only in EAT, and CD206 expression associated with that of macrophage identifying markers in all AT compartments (p < 0.001, all). In CHD patients, subjects with LDL-C above 1.8 mmol/L showed significantly higher NOS2 expression in PAT and EAT as compared to subjects with LDL-C levels below (p < 0.05), possibly reflecting increased cardiac AT pro-inflammatory activation. In SAT and PAT, CD206 expression associated with BMI in both CHD and CTRLs (p < 0.05, all), and with L-Gal9 in EAT, however only in CTRLs (p = 0.002).ConclusionCHD seems to be accompanied by an altered cardiac, and especially epicardial AT macrophage polarization. This may represent an important pathophysiological mechanism and a promising field of therapy targeting the excessive AT inflammation, in need of further investigation.

Sirtuin1, not NAMPT, possesses anti-inflammatory effects in epicardial, pericardial and subcutaneous adipose tissue in patients with CHD

“…This might be reflected in the observed positive correlation between SIRT1 and NOS2 in the different AT compartments, and as AT is vascularized, also the significant correlation between SIRT1 and the endothelial markers CD31 in SAT and PAT. NOS2 has recently been shown upregulated in EAT and PAT in these patients with LDL levels above the median value (1.8 mmol/L) [ 28 ]. The elevated SIRT1 expression in both SAT and PAT compared to EAT may be a consequence of the previously reported lower expressed IL-18 in these compartments compared to EAT [ 5 ].…”

“…The β2-microglobulin (Hs99999907_m1, Applied Biosystems) was used as the normalizer internal gene, and relative quantification of SIRT1 mRNA and NAMPT mRNA levels were determined applying the ΔΔCt method [ 26 ]. Gene expression of the NLRP3-related inflammatory markers (NLRP3, Caspase-1, IL-18, IL-1β, the macrophage polarization markers nitric oxide synthase 2 (NOS2) (Mɸ1) and scavenging mannose receptor CD206 (Mɸ2), and the cell markers cluster of differentiation ( CD) 3 (T-cells), CD31 (endothelial cells), CD68 and CD163 (macrophages), were previously analysed as indicated [ 27 , 28 ].…”

Epicardial Adipose Tissue Thickness and Preserved Ejection Fraction Heart Failure

“…Epicardial AT expansion is inversely related to perfusion of LV sub-endocardial layers and LV global longitudinal strain in patients with CAD; sub-endocardial layer perfusion and LV strain are directly related [41]. Analysis of macrophage polarization markers reveals increased low-grade inflammation in EAT biopsies from patients with CAD [42]. Epicardial AT inflammation and neo-angiogenesis correlate with the presence of noncalcified plaques and coronary calcifications in patients with and without obstructive CAD [38].…”

Exploring the Function of Epicardial Cells Beyond the Surface

“…Furthermore, epicardial adipose tissue (EAT) biopsies taken from patients with coronary artery disease showed alterations in macrophage polarization correlating with disease severity. 117 Retention of anti-inflammatory macrophages at the epicardium has been suggested to be crucial in preventing cardiac functional decline associated with aging. 118 However, further investigation must be done to determine whether differential macrophage identity contributes to coronary artery disease development.…”