Pivotal role of rho-associated kinase 2 in generating the intrinsic circadian rhythm of vascular contractility

Toshiro Saito, Mayumi Hirano, Tomomi Ide, Toshihiro Ichiki, Noriyuki Koibuchi, Kenji Sunagawa, Katsuya Hirano

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Background-The circadian variation in the incidence of cardiovascular events may be attributable to the circadian changes in vascular contractility. The circadian rhythm of vascular contractility is determined by the interplay between the central and peripheral clocks. However, the molecular mechanism of the vascular intrinsic clock that generates the circadian rhythm of vascular contractility still remains largely unknown. Methods and Results-The agonist-induced phosphorylation of myosin light chain in cultured smooth muscle cells synchronized by dexamethasone pulse treatment exhibited an apparent circadian oscillation, with a 25.4-hour cycle length. The pharmacological inhibition and knockdown of Rho-associated kinase 2 (ROCK2) abolished the circadian rhythm of myosin light chain phosphorylation. The expression and activity of ROCK2 exhibited a circadian rhythm in phase with that of myosin light chain phosphorylation. A clock gene, RORα, activated the promoter of the ROCK2 gene, whereas its knockdown abolished the rhythmic expression of ROCK2. In the mouse aorta, ROCK2 expression exhibited the circadian oscillation, with a peak at Zeitgeber time 0/24 and a nadir at Zeitgeber time 12. The myofilament Ca sensitization induced by GTPγS and U46619, a thromboxane A2 analog, at Zeitgeber time 0/24 was greater than that seen at Zeitgeber time 12. The circadian rhythm of ROCK2 expression and myofilament Ca sensitivity was abolished in staggerer mutant mice, which lack a functional RORα. Conclusions-ROCK2 plays a pivotal role in generating the intrinsic circadian rhythm of vascular contractility by receiving a cue from RORα. The ROCK2-mediated intrinsic rhythm of vascular contractility may underlie the diurnal variation of the incidence of cardiovascular diseases.

Original languageEnglish
Pages (from-to)104-114
Number of pages11
JournalCirculation
Volume127
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

Fingerprint

rho-Associated Kinases
Circadian Rhythm
Blood Vessels
Myosin Light Chains
Myofibrils
Phosphorylation
Neurologic Mutant Mice
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Thromboxane A2
Incidence
Dexamethasone
Genes
Smooth Muscle Myocytes
Cues
Aorta
Cardiovascular Diseases
Pharmacology

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Pivotal role of rho-associated kinase 2 in generating the intrinsic circadian rhythm of vascular contractility. / Saito, Toshiro; Hirano, Mayumi; Ide, Tomomi; Ichiki, Toshihiro; Koibuchi, Noriyuki; Sunagawa, Kenji; Hirano, Katsuya.

In: Circulation, Vol. 127, No. 1, 01.01.2013, p. 104-114.

Research output: Contribution to journalArticle

Saito, Toshiro ; Hirano, Mayumi ; Ide, Tomomi ; Ichiki, Toshihiro ; Koibuchi, Noriyuki ; Sunagawa, Kenji ; Hirano, Katsuya. / Pivotal role of rho-associated kinase 2 in generating the intrinsic circadian rhythm of vascular contractility. In: Circulation. 2013 ; Vol. 127, No. 1. pp. 104-114.
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