Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation

Eur Heart J. 2022 Jun 21;43(24):2317-2334. doi: 10.1093/eurheartj/ehac109.


Aims: Adverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Circadian nuclear receptor Rev-erbα is an essential and negative component of the circadian clock. To date, the expression profile and biological function of Rev-erbα in platelets have never been reported.

Methods and results: Here, we report the presence and functions of circadian nuclear receptor Rev-erbα in human and mouse platelets. Both human and mouse platelet Rev-erbα showed a circadian rhythm that positively correlated with platelet aggregation. Global Rev-erbα knockout and platelet-specific Rev-erbα knockout mice exhibited defective in haemostasis as assessed by prolonged tail-bleeding times. Rev-erbα deletion also reduced ferric chloride-induced carotid arterial occlusive thrombosis, prevented collagen/epinephrine-induced pulmonary thromboembolism, and protected against microvascular microthrombi obstruction and infarct expansion in an acute myocardial infarction model. In vitro thrombus formation assessed by CD41-labelled platelet fluorescence intensity was significantly reduced in Rev-erbα knockout mouse blood. Platelets from Rev-erbα knockout mice exhibited impaired agonist-induced aggregation responses, integrin αIIbβ3 activation, and α-granule release. Consistently, pharmacological inhibition of Rev-erbα by specific antagonists decreased platelet activation markers in both mouse and human platelets. Mechanistically, mass spectrometry and co-immunoprecipitation analyses revealed that Rev-erbα potentiated platelet activation via oligophrenin-1-mediated RhoA/ERM (ezrin/radixin/moesin) pathway.

Conclusion: We provided the first evidence that circadian protein Rev-erbα is functionally expressed in platelets and potentiates platelet activation and thrombus formation. Rev-erbα may serve as a novel therapeutic target for managing thrombosis-based cardiovascular disease.

Keywords: Blood platelets; Circadian; Platelet activation; Rev-erbα; Thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Platelets / metabolism
  • Circadian Clocks* / physiology
  • Circadian Rhythm / physiology
  • Humans
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism
  • Platelet Activation
  • Thrombosis*


  • Nuclear Receptor Subfamily 1, Group D, Member 1