Calcineurin and its regulator, RCAN1, confer time-of-day changes in susceptibility of the heart to ischemia/reperfusion

abstract Article history:Received 17 March 2014Received in revised form 25 April 2014Accepted 6 May 2014Available online 15 May 2014Keywords:Circadian rhythmsIschemia–reperfusionSignal transductionCalcineurinRcan1Cardioprotection Many important components of the cardiovascular system display circadian rhythmicity. In both humans andmice, cardiac damage from ischemia/reperfusion (I/R) is greatest at the transition from sleep to activity. Thecauses of this window of susceptibility are notfully understood. In the murineheart we havereportedhigham-plitudecircadianoscillationsintheexpressionofthecardioprotectiveproteinregulatorofcalcineurin1 (Rcan1).ThisstudywasdesignedtotestwhetherRcan1contributestothecircadianrhythmincardiacprotectionfromI/Rdamage. Wild type (WT), Rcan1 KO, and Rcan1-Tg mice, with cardiomyocyte-specific overexpression of Rcan1,were subjected to 45min of myocardial ischemia followed by 24h of reperfusion. Surgeries were performedei-therduringthefirst2h(AM)orduringthelast2h(PM)oftheanimal'slightphase.Theareaatriskwasthesamefor all genotypes at either time point; however, in WT mice, PM-generated infarcts were 78% larger than AM-generated infarcts. Plasma cardiac troponin I levels were likewise greater in PM-operated animals. In Rcan1 KOmice there was no significant difference between the AM- and PM-operated hearts, which displayed greater in-dicesofdamagesimilartothatofPM-operatedWTanimals.Micewithcardiomyocyte-specificoverexpressionofhuman RCAN1, likewise, showed notime-of-day difference,but had smallerinfarctscomparable to thoseof AM-operatedWTmice.Invitro,cardiomyocytesdepletedofRCAN1weremoresensitivetosimulatedI/Randthecal-cineurin inhibitor, FK506, restoredprotection. FK506 also conferred protection to PM-infarcted WT animals. Im-portantly, transcription of core circadian clock genes was not altered in Rcan1 KO hearts. These studies identifythe calcineurin/Rcan1-signaling cascade as a potential therapeutic target through which to benefitfrominnatecircadianchangesincardiacprotectionwithoutdisruptingcorecircadianoscillationsthatareessentialtocardio-vascular, metabolic, and mental health.© 2014 Elsevier Ltd. All rights reserved.