Publication Date:
2012-03-01
Description:
Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada's syndrome) of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, kruppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac arrhythmogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297978/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297978/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jeyaraj, Darwin -- Haldar, Saptarsi M -- Wan, Xiaoping -- McCauley, Mark D -- Ripperger, Jurgen A -- Hu, Kun -- Lu, Yuan -- Eapen, Betty L -- Sharma, Nikunj -- Ficker, Eckhard -- Cutler, Michael J -- Gulick, James -- Sanbe, Atsushi -- Robbins, Jeffrey -- Demolombe, Sophie -- Kondratov, Roman V -- Shea, Steven A -- Albrecht, Urs -- Wehrens, Xander H T -- Rosenbaum, David S -- Jain, Mukesh K -- HL054807/HL/NHLBI NIH HHS/ -- HL066991/HL/NHLBI NIH HHS/ -- HL075427/HL/NHLBI NIH HHS/ -- HL076754/HL/NHLBI NIH HHS/ -- HL084154/HL/NHLBI NIH HHS/ -- HL086548/HL/NHLBI NIH HHS/ -- HL086614/HL/NHLBI NIH HHS/ -- HL089598/HL/NHLBI NIH HHS/ -- HL091947/HL/NHLBI NIH HHS/ -- HL094660/HL/NHLBI NIH HHS/ -- HL097595/HL/NHLBI NIH HHS/ -- HL102241/HL/NHLBI NIH HHS/ -- HL76446/HL/NHLBI NIH HHS/ -- K24 HL076446/HL/NHLBI NIH HHS/ -- K99 HL102241/HL/NHLBI NIH HHS/ -- M01-RR02635/RR/NCRR NIH HHS/ -- R00 HL102241/HL/NHLBI NIH HHS/ -- R01 HL084154/HL/NHLBI NIH HHS/ -- R01 HL084154-04/HL/NHLBI NIH HHS/ -- R01 HL086548/HL/NHLBI NIH HHS/ -- R01 HL086548-05/HL/NHLBI NIH HHS/ -- R01 HL097593/HL/NHLBI NIH HHS/ -- R01 HL097593-03/HL/NHLBI NIH HHS/ -- R01 HL110630/HL/NHLBI NIH HHS/ -- R01 HL110630-02/HL/NHLBI NIH HHS/ -- England -- Nature. 2012 Feb 22;483(7387):96-9. doi: 10.1038/nature10852.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. darwinjeyaraj@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22367544" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Arrhythmias, Cardiac/complications/genetics/*physiopathology
;
Cells, Cultured
;
Circadian Rhythm/genetics/*physiology
;
DNA-Binding Proteins/deficiency/genetics/metabolism
;
Death, Sudden, Cardiac/etiology
;
Electrocardiography
;
Gene Expression Regulation
;
Heart Conduction System/*physiology
;
Heart Rate/physiology
;
Heart Ventricles/cytology
;
Kv Channel-Interacting Proteins/biosynthesis/genetics
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Muscle Cells/cytology
;
Promoter Regions, Genetic/genetics
;
Rats
;
Time Factors
;
Transcription Factors/deficiency/genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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