Angiotensin II type 1a receptor signalling directly contributes to the increased arrhythmogenicity in cardiac hypertrophy.
OBJECTIVE
Angiotensin II has been implicated in the development of various cardiovascular ailments, including cardiac hypertrophy and heart failure. The fact that inhibiting its signalling reduced the incidences of both sudden cardiac death and heart failure in several large-scale clinical trials suggests that angiotensin II is involved in increased cardiac arrhythmogenicity during the development of heart failure. However, because angiotensin II also promotes structural remodelling, including cardiomyocyte hypertrophy and cardiac fibrosis, it has been difficult to assess its direct contribution to cardiac arrhythmogenicity independently of the structural effects.


METHODS
We induced cardiac hypertrophy in wild-type (WT) and angiotensin II type 1a receptor knockout (AT1aR-KO) mice by transverse aortic constriction (TAC). The susceptibility to ventricular tachycardia (VT) assessed in an in vivo electrophysiological study was compared in the two genotypes. The effect of acute pharmacological blockade of AT1R on the incidences of arrhythmias was also assessed.


RESULTS
As described previously, WT and AT1aR-KO mice with TAC developed cardiac hypertrophy to the same degree, but the incidence of VT was much lower in the latter. Moreover, although TAC induced an increase in tyrosine phosphorylation of connexin 43, a critical component of gap junctional channels, and a reduction in ventricular levels of connexin 43 protein in both genotypes, the effect was significantly ameliorated in AT1aR-KO mice. Acute pharmacological blockade of AT1R also reduced the incidence of arrhythmias.


CONCLUSIONS
Our findings demonstrate that AT1aR-mediated signalling makes a direct contribution to the increase in arrhythmogenicity in hypertrophied hearts independently of structural remodelling.
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan; EBM Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Shinji
S
Yasuno
Koichiro
K
Kuwahara
Hideyuki
H
Kinoshita
Chinatsu
C
Yamada
Yasuaki
Y
Nakagawa
Satoru
S
Usami
Yoshihiro
Y
Kuwabara
Kenji
K
Ueshima
Masaki
M
Harada
Toshio
T
Nishikimi
Kazuwa
K
Nakao
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control
C544066:Agtr1a protein, mouse; D047228:Angiotensin II Type 1 Receptor Blockers; D000889:Anti-Arrhythmia Agents; C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D018031:Connexin 43; C543076:GJA1 protein, mouse; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; C568321:Scn5a protein, mouse
angiotensin; arrhythmia; connexin; hypertrophy