Laminar shear stress upregulates the expression of PPARs in vascular endothelial cells under high free fatty acid‑induced stress

Abstract

Shear stress has been reported to result in various metabolic effects in endothelial cells (ECs), which in turn contribute to the regulation of their vascular functions. Peroxisome proliferator-activated receptors (PPARs) have been reported to regulate lipid metabolism and have been implicated in metabolic disorders. The present study assessed the effects of laminar shear stress on the expression of PPARs in ECs in the presence of high concentrations of free fatty acids (FFAs). Human aortic ECs (HAECs) were treated with a high concentrations of palmitic acid (PA) and exposed to high shear stress (HSS) or low shear stress (LSS). Western blotting and ELISA were performed to quantify protein expression and assess prostacyclin production. The results revealed that long-term application of HSS to PA-treated HAECs induced PPAR-α,-δ and-γ protein expression. Additionally, LSS induced higher levels of PPAR-α protein expression in PA-treated HAECs compared with those after HSS. HAECs exposed to HSS also released prostacyclin (PGI 2). However, HAECs treated with high concentrations of PA also produced high levels of PGI 2 in the perfusion media in response to HSS compared with the static PA group. HSS also reduced the static PA-induced expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1. The results demonstrated that HAECs increases the expression of all three peroxisome proliferator-activated receptor isoforms in response to shear metabolic stress at high FFA concentrations. The present study may provide preliminary insights into the potential roles of PPARs as an effective treatment method against metabolic disturbances that can result in EC dysfunction.

Exercise mitigates flow recirculation and activates metabolic transducer SCD1 to catalyze vascular protective metabolites

“…PPARs belong to the nuclear receptor superfamily of ligandactivated transcription factors regulating lipid and glucose metabolism, energy homeostasis, and inflammation (73). Previous studies have demonstrated that shear stress induces PPARα, PPARδ, and PPARγ to regulate endothelial function (74,75). PPARγ agonists belong to the thiazolidinedione class of drugs such as troglitazone and rosiglitazone that attenuate palmitate-induced ER stress and apoptosis by activating SCD1 induction in macrophages (76).…”

Diversity of Lipid Function in Atherogenesis: A Focus on Endothelial Mechanobiology

“…Shear stress during laminar flow increases the expression of LXRs in endothelial cells through the PPARγ pathway, which is induced by laminar flow [ 290 , 291 ]. It was shown that the expression of LXRa, LXRβ and their target genes is higher in the endothelium of the mouse thoracic aorta, where laminar blood flow is assumed, than in areas with impaired flow, for example, in the aortic arch region [ 292 ].…”

Shear Stress and the AMP-Activated Protein Kinase Independently Protect the Vascular Endothelium from Palmitate Lipotoxicity

“…In an in vivo setting, endothelial cells (EC) encounter blood flow-mediated shear stress of variable intensity and pattern, which has profound effects on multiple EC functions including gene expression and metabolism [21][22][23][24][25][26][27]. Laminar pulsatile shear stress generated in straight vascular regions is protective for the endothelium, whereas turbulent/oscillatory shear stress in branches of the conduit arteries is associated with atherogenesis [21,23,26,28,29].…”

“…Laminar pulsatile shear stress generated in straight vascular regions is protective for the endothelium, whereas turbulent/oscillatory shear stress in branches of the conduit arteries is associated with atherogenesis [21,23,26,28,29]. In particular, laminar shear stress confers protection against FFA lipotoxicity via decreased ROS generation, downregulation of inflammatory cascades, and antiapoptotic action [27,[30][31][32][33][34].…”