Peroxisome proliferator-activated receptors (PPARs) have been identified as key endothelial signaling molecules regulating lipid metabolism, and contributing to the metabolic derangements associated with Type 2 Diabetes. We investigated whether PPARβ activation can prevent palmitate-induced endothelial dysfunction using ex vivo and in vitro models, focusing on the rate-limiting enzyme for beta-oxidation, carnitine palmitoyl transferase (CPT)-1.
Acetylcholine-induced endothelium-dependent relaxation in mouse thoracic aortic (MTA) rings was measured using wire myography, and mouse aortic endothelial cell (MAEC) function was assessed in the presence or absence of palmitate, with or without the PPARβ agonist and antagonist, GW0742(1 µM), or GSK0660(1 µM) respectively. MAECs were also transfected with control or CPT-1-specific siRNA. Nitric oxide (NO) and reactive oxygen species (ROS) production was measured using DAF and DHE respectively, while western blotting and RT-PCR was used to assess eNOS and CPT-1 expression respectively.
Palmitate impairs endothelium-dependent relaxation to acetylcholine and attenuates eNOS phosphorylation in MTA, also reducing A23187-stimulated NO, and increasing ROS production in MAECs. GW0742 improved endothelial function, increased NO production and suppressed ROS generation induced by palmitate. RT-PCR demonstrated a marked increase of CPT-1 expression in GW0742-treated MAECs, an effect abolished by GSK0660 or the CPT-1 inhibitor etomoxir. CPT-1 siRNA, also blunted i) CPT-1 up-regulation, ii) elevated NO bioavailability, and iii) reduction in ROS generation induced by GW0742, in palmitate-treated MAECs.
PPARβ activation protects against palmitate-induced endothelial dysfunction ex vivo and attenuates the damage in activated MAECs in vitro. These novel cytoprotective effects appear to operate via increased beta-oxidation resulting from CPT-1 up-regulation.
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