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AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats
Kohzo Nagata1, Fuji Somura, Koji Obata
1Department of Clinical Pathophysiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Insights
Blockade of the angiotensin II type 1 receptor reduces cardiac hypertrophy and fibrosis in salt-sensitive rats by inhibiting calcineurin activation, independent of blood pressure changes.
Area of Science:
- Cardiovascular Research
- Renal Physiology
- Molecular Cardiology
Background:
- Dahl salt-sensitive (DS) rats develop hypertension, cardiac hypertrophy, and fibrosis when fed a high-salt diet.
- Calcineurin activity and expression are elevated in the hearts of DS rats.
- Angiotensin II type 1 (AT1) receptor signaling and transforming growth factor-beta1 (TGF-beta1) are implicated in cardiac remodeling.
Purpose of the Study:
- To investigate the role of calcineurin in mediating cardiac hypertrophy and fibrosis attenuation by AT1 receptor blockade.
- To examine the effects of the calcineurin inhibitor FK506 on cardiac remodeling in DS rats.
- To elucidate the relationship between AT1 receptor blockade, calcineurin, and TGF-beta1 signaling in vivo.
Main Methods:
- DS rats were fed a high-salt diet and treated with candesartan (AT1 receptor blocker) or FK506 (calcineurin inhibitor).
- Cardiac hypertrophy, fibrosis, calcineurin activity, and mRNA expression of ACE and TGF-beta1 were assessed.
- Cardiac function and expression of fetal-type cardiac genes were evaluated.
Main Results:
- Both candesartan and FK506 attenuated cardiac hypertrophy, fibrosis, and calcineurin activation without affecting cardiac function or blood pressure.
- Candesartan, but not FK506, prevented the upregulation of angiotensin-converting enzyme (ACE) and TGF-beta1 gene expression.
- Both treatments inhibited the induction of fetal-type cardiac genes.
Conclusions:
- AT1 receptor blockade attenuates cardiac hypertrophy and fibrosis in salt-sensitive hypertension via calcineurin inhibition, independent of antihypertensive effects.
- Calcineurin activation is downstream of TGF-beta1 in AT1 receptor-mediated angiotensin II signaling.
- Targeting the AT1 receptor-calcineurin pathway offers a potential therapeutic strategy for preventing cardiac remodeling.
Abstract:
The possible role of calcineurin in the attenuation of cardiac hypertrophy and fibrosis by blockade of the angiotensin II type 1 (AT1) receptor was investigated in Dahl salt-sensitive (DS) rats. The effect of the calcineurin inhibitor FK506 was also studied. DS rats progressively developed severe hypertension when fed a diet containing 8% NaCl from 7 weeks of age. In addition, marked cardiac hypertrophy and fibrosis were apparent and the activity of calcineurin and its mRNA expression in the myocardium was increased in these animals at 12 weeks in comparison with age-matched Dahl salt-resistant rats. The abundance of angiotensin-converting enzyme (ACE) and transforming growth factor (TGF)-beta1 mRNAs was also increased in the hearts of DS rats at 12 weeks. Treatment of DS rats with a non-antihypertensive dose of the selective AT1 receptor blocker candesartan (1 mg/kg per day) or FK506 (0.1 mg/kg per day) from 7 to 12 weeks attenuated both calcineurin activity and its mRNA expression in the heart, as well as the development of cardiac hypertrophy and fibrosis, without affecting cardiac function. Treatment with candesartan, but not FK506, prevented the upregulation of ACE and TGF-beta1 gene expression. Both candesartan and FK506 prevented the load-induced induction of fetal-type cardiac genes. These results demonstrate that AT1 receptor blockade attenuates the development of cardiac hypertrophy and fibrosis as well as the activation of calcineurin, without an antihypertensive effect, in rats with salt-sensitive hypertension. Calcineurin may be downstream from TGF-beta1 in AT1 receptor-mediated angiotensin II signaling in vivo.