Inhibitory Effect of α-Lipoic Acid on Platelet Aggregation Is Mediated by PPARs

Abstract

Peroxisome proliferator-activated receptors (PPARs) isoforms (α, β/δ, and γ are present in human platelets, and activation of PPARs inhibits platelet aggregation. α-Lipoic acid (ALA), occurring naturally in human food, has been reported to exhibit an antiplatelet activity. However, the mechanisms underlying ALA-mediated inhibition of platelet aggregation remain unknown. The aim of this study was to investigate whether the antiplatelet activity of ALA is mediated by PPARs. ALA itself significantly induced PPARα/γ activation in platelets and increased intracellular amounts of PPARα/γ by blocking PPARα/γ secretion from arachidonic acid (AA)-activated platelets. Moreover, ALA significantly inhibited AA-induced platelet aggregation, Ca(2+) mobilization, and cyclooxygenase-1 (COX-1) activity, but increased cyclic AMP production in rabbit washed platelets. Importantly, ALA also enhanced interaction of PPARα/γ with protein kinase Cα (PKCα) and COX-1 accompanied by an inhibition of PKCα activity in resting and AA-activated platelets. However, the above effects of ALA on platelets were markedly reversed by simultaneous addition of selective PPARα antagonist (GW6471) or PPARγ antagonist (GW9662). Taken together, the present study provides a novel mechanism by which ALA inhibition of platelet aggregation is mediated by PPARα/γ-dependent processes, which involve interaction with PKCα and COX-1, increase of cyclic AMP formation, and inhibition of intracellular Ca(2+) mobilization.

Mechanisms of antiplatelet activity of nifedipine

“…These findings support our hypothesis that PPAR-b/-g-mediated processes contribute to the antiplatelet activity of nifedipine. Many studies have described that PPAR-activating agents inhibit platelet aggregation [13,14]. Consistent with previous findings that nifedipine activates PPAR-g in macrophages [15], our results showed that nifedipine is a dual PPAR-b/-g agonist in platelets, as evidenced by significantly increased platelet PPAR-b/-g activity after nifedipine treatment.…”

“…Our previous study showed that the PPAR-a/-g inhibit platelet PKC-a activation through their association with PKC-a [14]. In this study, we identified that nifedipine also induces the interaction between PPAR-b/-g and PKC-a in activated platelets, leading to reduced PKC-a phosphorylation in the complex.…”

“…After centrifugation, the supernatants were used to evaluate the activity of the PPARs using a PPAR transcription factor ELISA kit, and the absorbance was read at 450 nm [14].…”

“…Three PPAR isoforms (PPAR-a, PPAR-b/d, and PPAR-g) exist in human platelets. Our previous studies have shown that PPAR-g, PPAR-a, and PPAR-a/-g mediate the antiplatelet activities of simvastatin, fenofibrate, and alpha-lipoic acid, respectively [13,14]. Therefore, reagents exerting PPAR-activating activity could potentially provide an antiplatelet treatment.…”

Inhibition of adenosine diphosphate-induced platelet aggregation by alpha-lipoic acid and dihydroquercetin in vitro

“…[7] Investigators link the antiplatelet activity of α-LA with an elevation of cyclic adenosine monophosphate (cAMP) formation, involving the subsequent inhibition of Thromboxane A2 (TXA 2 ), cyclooxygenase-1, protein kinase Cα-mediated pathways, peroxisome proliferator-activated receptors (PPARγ), Ca 2+ mobilization and inhibition of reactive oxygen species formation, and the increase of platelet membrane fluidity. [717]…”