Cardiac overexpression of constitutively active Galpha q causes angiotensin II type1 receptor activation, leading to progressive heart failure and ventricular arrhythmias in transgenic mice.

Naoko Matsushita,Mitsuhiko Yamada,Tsutomu Nakada,Yasuchika Takeishi,Atsushi Sanbe,Satoshi Suzuki,Toshihide Kashihara,Hisashi Shimojo,Ulrike Mende,Ulrike Mende,Eiichi Taira,Masamichi Hirose,Junichi Sadoshima

doi:10.1371/journal.pone.0106354

Abstract

BackgroundTransgenic mice with transient cardiac expression of constitutively active Galpha q (Gαq-TG) exhibt progressive heart failure and ventricular arrhythmias after the initiating stimulus of transfected constitutively active Gαq becomes undetectable. However, the mechanisms are still unknown. We examined the effects of chronic administration of olmesartan on heart failure and ventricular arrhythmia in Gαq-TG mice.Methodology/Principal FindingsOlmesartan (1 mg/kg/day) or vehicle was chronically administered to Gαq-TG from 6 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic olmesartan administration prevented the severe reduction of left ventricular fractional shortening, and inhibited ventricular interstitial fibrosis and ventricular myocyte hypertrophy in Gαq-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 9 of 10 vehicle-treated Gαq-TG but in none of 10 olmesartan-treated Gαq-TG. The collected QT interval and monophasic action potential duration in the left ventricle were significantly shorter in olmesartan-treated Gαq-TG than in vehicle-treated Gαq-TG. CTGF, collagen type 1, ANP, BNP, and β-MHC gene expression was increased and olmesartan significantly decreased the expression of these genes in Gαq-TG mouse ventricles. The expression of canonical transient receptor potential (TRPC) 3 and 6 channel and angiotensin converting enzyme (ACE) proteins but not angiotensin II type 1 (AT1) receptor was increased in Gαq-TG ventricles compared with NTG mouse ventricles. Olmesartan significantly decreased TRPC6 and tended to decrease ACE expressions in Gαq-TG. Moreover, it increased AT1 receptor in Gαq-TG.Conclusions/SignificanceThese findings suggest that angiotensin II type 1 receptor activation plays an important role in the development of heart failure and ventricular arrhythmia in Gαq-TG mouse model of heart failure.

Highlights

Our previous study showed that transient expression of a constitutively active the GTP-binding protein aq subunit in hearts of transgenic mice (Gaq-TG mice) is sufficient to induce cardiac hypertrophy and heart failure (HF) [1]
We found that angiotensin converting enzyme (ACE) but not ACE2 and angiotensin II type 1 (AT1) receptor protein expression was increased in vehicle-treated GaqTG mouse hearts
Chronic administration of olmesartan for 26 weeks prevented the progression of heart failure and ventricular arrhythmia in Gaq-TG mice

Summary

Introduction

Our previous study showed that transient expression of a constitutively active the GTP-binding protein aq subunit in hearts of transgenic mice (Gaq-TG mice) is sufficient to induce cardiac hypertrophy and heart failure (HF) [1]. Our more recent studies demonstrated that diacylglycerol kinase zeta, which catalyzes DAG, rescues HF [2] and inhibited atrial [3] and ventricular [4] arrhythmias in Gaq-TG mice, suggesting that DAG plays a critical role in the development of cardiac hypertrophy and HF in this mouse model. It is still unknown what factors act upstream of DAG. We examined the effects of chronic administration of olmesartan on heart failure and ventricular arrhythmia in Gaq-TG mice

Methods

Results

Conclusion