Dataset Information

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

ABSTRACT:

Background

Transgenic mice with transient cardiac expression of constitutively active Galpha q (G?q-TG) exhibt progressive heart failure and ventricular arrhythmias after the initiating stimulus of transfected constitutively active G?q becomes undetectable. However, the mechanisms are still unknown. We examined the effects of chronic administration of olmesartan on heart failure and ventricular arrhythmia in G?q-TG mice.

Methodology/principal findings

Olmesartan (1 mg/kg/day) or vehicle was chronically administered to G?q-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 G?q-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 9 of 10 vehicle-treated G?q-TG but in none of 10 olmesartan-treated G?q-TG. The collected QT interval and monophasic action potential duration in the left ventricle were significantly shorter in olmesartan-treated G?q-TG than in vehicle-treated G?q-TG. CTGF, collagen type 1, ANP, BNP, and ?-MHC gene expression was increased and olmesartan significantly decreased the expression of these genes in G?q-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 G?q-TG ventricles compared with NTG mouse ventricles. Olmesartan significantly decreased TRPC6 and tended to decrease ACE expressions in G?q-TG. Moreover, it increased AT1 receptor in G?q-TG.

Conclusions/significance

These findings suggest that angiotensin II type 1 receptor activation plays an important role in the development of heart failure and ventricular arrhythmia in G?q-TG mouse model of heart failure.

SUBMITTER: Matsushita N

PROVIDER: S-EPMC4149533 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

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

Matsushita Naoko N Kashihara Toshihide T Shimojo Hisashi H Suzuki Satoshi S Nakada Tsutomu T Takeishi Yasuchika Y Mende Ulrike U Taira Eiichi E Yamada Mitsuhiko M Sanbe Atsushi A Hirose Masamichi M

PloS one 20140829 8

<h4>Background</h4>Transgenic 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.<h4>Methodology/principal findings</h4>Olmesartan (1 mg/kg/day) or v ...[more]

PMID: 25171374

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Project description:BackgroundBeneficial effects of nicorandil on the treatment of hypertensive heart failure (HF) and ischemic heart disease have been suggested. However, whether nicorandil has inhibitory effects on HF and ventricular arrhythmias caused by the activation of G protein alpha q (Gα(q)) -coupled receptor (GPCR) signaling still remains unknown. We investigated these inhibitory effects of nicorandil in transgenic mice with transient cardiac expression of activated Gα(q) (Gα(q)-TG).Methodology/principal findingsNicorandil (6 mg/kg/day) or vehicle was chronically administered to Gα(q)-TG from 8 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic nicorandil administration prevented the severe reduction of left ventricular fractional shortening and inhibited ventricular interstitial fibrosis in Gα(q)-TG. SUR-2B and SERCA2 gene expression was decreased in vehicle-treated Gα(q)-TG but not in nicorandil-treated Gα(q)-TG. eNOS gene expression was also increased in nicorandil-treated Gα(q)-TG compared with vehicle-treated Gα(q)-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 7 of 10 vehicle-treated Gα(q)-TG but in none of 10 nicorandil-treated Gα(q)-TG. The QT interval was significantly shorter in nicorandil-treated Gα(q)-TG than vehicle-treated Gα(q)-TG. Acute nicorandil administration shortened ventricular monophasic action potential duration and reduced the number of PVCs in Langendorff-perfused Gα(q)-TG mouse hearts. Moreover, HMR1098, a blocker of cardiac sarcolemmal K(ATP) channels, significantly attenuated the shortening of MAP duration induced by nicorandil in the Gα(q)-TG heart.Conclusions/significanceThese findings suggest that nicorandil can prevent the development of HF and ventricular arrhythmia caused by the activation of GPCR signaling through the shortening of the QT interval, action potential duration, the normalization of SERCA2 gene expression. Nicorandil may also improve the impaired coronary circulation during HF.

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Dataset Information

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

Background

Methodology/principal findings

Conclusions/significance

Publications

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

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