Renin-angiotensin system component expression in the HL-1 atrial cell line and in a pig model of atrial fibrillation.
OBJECTIVE
Local atrial tissue angiotensin II (AngII) level is elevated in atrial fibrillation (AF), but the mechanism is unknown. We hypothesized that atrial myocytes express all components of the renin-angiotensin system (RAS) and investigated whether rapid depolarization alone is sufficient to increase paracrine AngII production by up-regulating RAS component expression.


METHODS
In the HL-1 atrial cell line, rapid depolarization was induced by rapid field electrical stimulation (RES) at 1.0 V/cm and 600/min (10 Hz) in atrial HL-1 cells. In a pig model of AF, AF was induced by atrial pacing at 600/min in 10 adult pigs and 10 sham-operated pigs for comparison.


RESULTS
In atrial myocytes, RES induced a sustained elevation of intracellular calcium, and up-regulation of angiotensin-converting enzyme (ACE), chymase and angiotensinogen, resulting in increased AngII production. RES-induced AngII production was attenuated by enalapril [ACE inhibitor (ACEI)] and chymostatin (chymase inhibitor). Conditioned medium from RES-stimulated atrial myocytes increased [3H]leucine uptake and atrial natriuretic peptide expression in atrial myocytes, and [3H]proline uptake and collagen type 1 alpha 1 expression in atrial fibroblasts. Both were attenuated by co-incubation with the AngII type 1 receptor blocker (ARB) losartan. In the porcine model, significant structural changes and a similar pattern of changes of RAS components were noted in AF pigs.


CONCLUSIONS
Atrial cells expressed all components of RAS and rapid depolarization alone was sufficient to up-regulate RAS components, increase paracrine AngII production and induce atrial structural changes, which are attenuated by ACEI, ARB and chymase inhibitor.
Tsai
Chia-Ti
CT
Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Lai
Ling-Ping
LP
Hwang
Juey-Jen
JJ
Chen
Wen-Pin
WP
Chiang
Fu-Tien
FT
Hsu
Kuan-Lih
KL
Tseng
Chuen-Den
CD
Tseng
Yung-Zu
YZ
Lin
Jiunn-Lee
JL
D000804:Angiotensin II / Q000096:biosynthesis*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism / Q000503:physiopathology*; D002460:Cell Line; D004195:Disease Models, Animal; D004558:Electric Stimulation; D015870:Gene Expression; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000235:genetics*; D013552:Swine; D015854:Up-Regulation
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000804:Angiotensin II