Lysophosphatidic acid causes endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells

AimThe objective of this study was to determine the effects of lysophosphatidic acid (LPA) on endothelial functions and molecular alternations in both porcine coronary arteries and human coronary artery endothelial cells (HCAECs).Methods and resultsThe vessel rings and HCAECs were treated with clinically relevant concentrations of LPA for different times. Vasomotor reactivity was studied with a myograph tension system. LPA (10 and 50 μM) treatment for the vessel rings significantly reduced endothelium-dependent vasorelaxation in response to bradykinin (×10−5 M) by 32% and 49%, respectively, compared with the control (P < 0.05). LPA decreased endothelial nitric oxide synthase (eNOS) mRNA and immunoreactivity levels in the vessel rings. In HCAECs, LPA reduced eNOS mRNA, phospho-eNOS and total eNOS protein levels. In addition, superoxide anion levels in LPA-treated vessel rings and HCAECs were significantly increased by lucegenin-enhanced chemiluminescence assay and dihydroethidium staining, respectively. Mitochondrial membrane potential and ATP content in LPA-treated HCAECs were substantially decreased. The mRNA levels of reactive oxygen species generating enzymes NOX4 and p40phox were increased, while endogenous antioxidant enzyme superoxide dismutase 1 was decreased in response to LPA treatment in HCAECs. Furthermore, exogenous antioxidant molecule selenomethionine (SeMet) effectively reversed these LPA-induced effects in both porcine coronary arteries and HCAECs.ConclusionsLPA causes endothelial dysfunction by a mechanism associated with decreased eNOS expression and increased oxidative stress in porcine coronary arteries and HCAECs.

► Lysophosphatidic acid reduces endothelium-dependent vasorelaxation in porcine coronary arteries. ► Lysophosphatidic acid decreases the expression of endothelial nitric oxide synthase in both porcine coronary arteries and human coronary artery endothelial cells. ► Lysophosphatidic acid increases oxidative stress in both porcine coronary arteries and human coronary artery endothelial cells.