Role of PGE₂ on MMP density in human vessels and their perivascular adipose tissue under inflammatory conditions

X. Norel¹, C. Deschildre¹, G. Topal², P. Jakobsson³, D. Longrois¹, J. E. Fabre¹, G. Ozen¹. ¹LVTS, Eicosanoids & Vascular Pharmacology, INSERM U1148, Paris, France, ²Faculty of Pharmacy, Department of Pharmacology, Istanbul University,, Istanbul, Turkey, ³Unit of Rheumatology, Department of Medicine Solna,, Karolinska Institutet and Unit of Rheumatology, Stockolm, Sweden.

Introduction: Matrix metalloproteinases (MMPs) are responsible for the degradation of extracellular matrix components in particular inflammatory process such as pathogenesis of atherosclerosis in coronary artery (CA) or graft failure of coronary artery bypass grafts [(internal mammary artery (IMA), saphenous vein (SV)]. Prostaglandin E₂ (PGE₂) is synthesized by vascular wall or perivascular adipose tissue (PVAT) mainly via microsomal PGE synthase-1 (mPGES-1). This enzyme can be induced under inflammatory conditions. The aim of the study was to investigate whether MMPs and the endogenous tissue inhibitors of metalloproteinase (TIMPs) may be regulated by PGE₂ under inflammatory conditions in either human vessels (CA, IMA or SV) or their isolated PVAT.

Method: Human CA and their isolated PVAT were obtained after heart transplantation for myocardial ischemia (Atherosclerotic, n=6) or non-ischemic cardiomyopathy (Non-atherosclerotic preparations, n=8). SV (n=10) and IMA (n=16) were obtained after coronary artery bypass surgery ( %25 female and %75 male patients). These vascular preparations and their PVAT were cultured (in RPMI and PSA) under inflammatory conditions (18h in the presence or absence of both interleukin-1beta (IL-1β, 100 ng/ml) and lipopolysaccharide (LPS, 100 μg/ml)). In addition, some preparations under inflammatory conditions were co-incubated with a selective mPGES-1 inhibitor (Compund III, 10 μM) (1). The release of MMP-1, -2; TIMP-1, -2 and PGE₂ were measured by ELISA in supernatants. Data are given as mean±SEM (n patients) and comparisons were performed using paired or unpaired Student’s t-test. Values were considered significantly different when P<0.05.

Results: The release of MMP-2 was greater than MMP-1 and both were significantly increased in atherosclerotic CA and PVAT versus non-atherosclerotic preparations (MMP-2 levels: Atherosclerotic CA: 619±178, PVAT: 434±124; Non-atherosclerotic CA: 246±56, PVAT: 138±35 pg/mg of wet weight tissue, P<0.05). An increase of MMP-1,-2 and a decrease of TIMP-1 have been observed under inflammatory conditions only in vascular wall of CA, IMA SV but not in their PVAT. The significant increase of PGE₂, MMP-1 and MMP-2 levels observed in inflammatory conditions were reversed by mPGES-1 inhibitor. Both vascular wall and PVAT of SV exhibited greater MMP release and PGE₂ levels versus IMA and CA.

Conclusions: These results suggest that MMP levels are up-regulated by PGE₂ in vascular wall of CA and bypass grafts under inflammatory conditions. Greater MMP activity observed in SV may contribute to the increased prevalence of graft failure in SV compared with IMA grafts following coronary artery bypass surgery.

References:

(1) Ozen G et al. (2017). Br J Pharmacol