l-Palmitoylcarnitine potentiates plasmin and tPA to inhibit thrombosis

Abstract

Abstract l-Palmitoylcarnitine (L-PC) is an important endogenous fatty acid metabolite. Its classical biological functions are involved in the regulations of membrane molecular dynamics and the β-oxidation of fatty acids. Decreased plasma long-chain acylcarnitines showed the association of venous thrombosis, implying anticoagulant activity of the metabolites and inspiring us to investigate if and how L-PC, a long-chain acylcarnitine, takes part in coagulation. Here we show that L-PC exerted anti-coagulant effects by potentiating the enzymatic activities of plasmin and tissue plasminogen activator (tPA). L-PC directly interacts with plasmin and tPA with an equilibrium dissociation constant (KD) of 6.47 × 10–9 and 4.46 × 10–9 M, respectively, showing high affinities. In mouse model, L-PC administration significantly inhibited FeCl3-induced arterial thrombosis. It also mitigated intracerebral thrombosis and inflammation in a transient middle cerebral artery occlusion (tMCAO) mouse model. L-PC induced little bleeding complications. The results show that L-PC has anti-thrombotic function by potentiating plasmin and tPA. Graphical Abstract

Keywords

• l-palmitoylcarnitine
• Coagulation
• Plasmin
• Tissue-type plasminogen activator
• Thrombosis