Circadian gene expression of clock genes and plasminogen activator inhibitor-1 in heart and aorta of spontaneously hypertensive and Wistar-Kyoto rats.
OBJECTIVE
Heart and aorta possess biologic clocks, but their involvement in genetic hypertension has been unknown. Plasminogen activator inhibitor-1 (PAI-1) expression is directly regulated by clock genes, while angiotensin II modulates both PAI-1 and clock gene expression. We therefore examined circadian expression of PAI-1 and clock genes, and effects of angiotensin type 1 (AT1) receptor antagonism, in heart and aorta of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats.


METHODS
We examined cardiac and aortic mRNA expression for PAI-1 and clock genes (Per2, Bmal1, Clock, and Dbp) every 4 h throughout the day by quantitative reverse transcription-polymerase chain reaction, and intervention with the AT1 receptor antagonist candesartan and equihypotensive hydralazine.


RESULTS
Cardiac PAI-1 expression was high in the dark, while aortic PAI-1 expression was high in the light. Both cardiac and aortic PAI-1 expression were greater in SHR than in WKY rats. Candesartan treatment decreased cardiac PAI-1 expression only in the dark in WKY rats but throughout the day in SHR. Candesartan but not hydralazine strongly attenuated circadian fluctuation of aortic PAI-1 mRNA in SHR and WKY rats. Clock genes oscillated synchronously in heart and aorta of SHR and WKY rats. Clock gene expression was increased in heart but not aorta of SHR. Candesartan did not affect clock gene expression.


CONCLUSIONS
Enhanced expression of clock genes may increase PAI-1 expression in concert with activated renin-angiotensin system in SHR heart. Rather than clock genes, the renin-angiotensin system induces daily fluctuation and increased expression of aortic PAI-1 mRNA in SHR.
Naito
Yoshiro
Y
Department of Internal Medicine, Cardiovascular Division, Hyogo College of Medicine, Nishinomiya, Japan.
Tsujino
Takeshi
T
Kawasaki
Daizo
D
Okumura
Takahiro
T
Morimoto
Shinji
S
Masai
Miho
M
Sakoda
Tsuyoshi
T
Fujioka
Yoshio
Y
Ohyanagi
Mitsumasa
M
Iwasaki
Tadaaki
T
D056930:ARNTL Transcription Factors; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D056926:CLOCK Proteins; D006332:Cardiomegaly / Q000188:drug therapy / Q000503:physiopathology; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000235:genetics*; D004268:DNA-Binding Proteins; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000502:physiology*; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D056950:Period Circadian Proteins; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013777:Tetrazoles / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
D056930:ARNTL Transcription Factors; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D051792:Basic Helix-Loop-Helix Proteins; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D013777:Tetrazoles; D015534:Trans-Activators; D014157:Transcription Factors; C485975:DBP protein, rat; C513311:Per2 protein, rat; C538945:Clock protein, rat; C081643:candesartan