Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 170, Issue 7, Pages 1384-1395Publisher
WILEY-BLACKWELL
DOI: 10.1111/bph.12328
Keywords
angiotensin; arrhythmia; hypertrophy; connexin
Categories
Funding
- Japan Society for the Promotion of Science
- Labor and Welfare
- Japan Heart Foundation/Pfizer Pharmaceuticals Inc
- Japan Heart Foundation/Novartis Grant for Research Award on Molecular and Cellular Cardiology
- MSD
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Uehara Memorial Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Mitsubishi Foundation
- Suzuken Memorial Foundation
- Kanae Foundation for the Promotion of Medical Science
- Takeda Medical Research Foundation
- Takeda Science Foundation
- Hoh-ansha Foundation
- SENSHIN Medical Research Foundation
- Grants-in-Aid for Scientific Research [25460749, 25860596, 21229013] Funding Source: KAKEN
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Background and PurposeAngiotensin 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. Experimental ApproachWe 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. Key ResultsAs 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 and ImplicationsOur findings demonstrate that AT1aR-mediated signalling makes a direct contribution to the increase in arrhythmogenicity in hypertrophied hearts independently of structural remodelling.
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