Functional cyclophilin D moderates platelet adhesion, but enhances the lytic resistance of fibrin

Sci Rep. 2018 Mar 29;8(1):5366. doi: 10.1038/s41598-018-23725-4.

Abstract

In the course of thrombosis, platelets are exposed to a variety of activating stimuli classified as 'strong' (e.g. thrombin and collagen) or 'mild' (e.g. ADP). In response, activated platelets adhere to injured vasculature, aggregate, and stabilise the three-dimensional fibrin scaffold of the expanding thrombus. Since 'strong' stimuli also induce opening of the mitochondrial permeability transition pore (MPTP) in platelets, the MPTP-enhancer Cyclophilin D (CypD) has been suggested as a critical pharmacological target to influence thrombosis. However, it is poorly understood what role CypD plays in the platelet response to 'mild' stimuli which act independently of MPTP. Furthermore, it is unknown how CypD influences platelet-driven clot stabilisation against enzymatic breakdown (fibrinolysis). Here we show that treatment of human platelets with Cyclosporine A (a cyclophilin-inhibitor) boosts ADP-induced adhesion and aggregation, while genetic ablation of CypD in murine platelets enhances adhesion but not aggregation. We also report that platelets lacking CypD preserve their integrity in a fibrin environment, and lose their ability to render clots resistant against fibrinolysis. Our results indicate that CypD has opposing haemostatic roles depending on the stimulus and stage of platelet activation, warranting a careful design of any antithrombotic strategy targeting CypD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / metabolism*
  • Animals
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism*
  • Cyclophilin D
  • Cyclophilins / genetics
  • Cyclophilins / physiology*
  • Cyclosporine / pharmacology*
  • Fibrin / metabolism
  • Fibrinolysis* / drug effects
  • Fibrinolysis* / physiology
  • Gene Knockout Techniques
  • Healthy Volunteers
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Platelet Activation
  • Platelet Adhesiveness
  • Reactive Oxygen Species / metabolism

Substances

  • Cyclophilin D
  • Mitochondrial Membrane Transport Proteins
  • PPIF protein, mouse
  • Reactive Oxygen Species
  • mitochondrial permeability transition pore
  • Adenosine Diphosphate
  • Cyclosporine
  • Fibrin
  • Cyclophilins
  • PPID protein, human