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Retinoid X receptor agonists inhibit hypertension-induced myocardial hypertrophy by modulating LKB1/AMPK/p70S6K
Jiang Zhu1, Ruo-Bing Ning1, Xiao-Yan Lin2
1First Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China;
Background:
Retinoid X receptor (RXR) has been demonstrated to play an important role in cardiac development and has been implicated in cardiovascular diseases. This study aimed to examine the effects of RXRα agonist bexarotene on pathological left ventricular hypertrophy (LVH) in a spontaneously hypertensive rat (SHR) model and the underlying mechanism.
Methods:
WKY rats served as controls. SHRs were randomized into 3 groups at the age of 4 weeks and were treated (once daily for 12 weeks) with either bexarotene (30 or 100mg/kg body weight) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Neonatal cardiomyocytes were treated with AngII (10(-7) mmol/L) with or without the indicated concentration of RXRα ligand 9-cis-RA. The protein abundances of β-actin, RXRα, LKB1, phospho-LKB1, AMPK, phospho-AMPK, P70S6K, phospho-P70S6K, ACE, and AT1 receptor were measured along with blood pressure, body weight and angiotensin II (Ang II) levels. The effects of LKB1 downregulation by LKB1 small, interfering RNA were examined.
Results:
Treatment of SHRs with bexarotene resulted in significant inhibition of LVH without eliminating hypertension. Immunoblot with heart tissue homogenates from SHRs revealed that bexarotene activated the LKB1/AMPK signaling pathway and inhibited p70S6K. However, the increased Ang II levels in SHR serum and heart tissue were not reduced by bexarotene treatment. Treatment of cardiomyocytes with Ang II resulted in significantly reduced LKB1/AMPK activity and increased p70S6K activity. 9-cis-RA antagonized Ang II-induced LKB1/AMPK and p70S6K activation changes in vitro.
Conclusions:
RXR agonists prevent the inhibition of the LKB1/AMPK/p70S6K pathway and regulate protein synthesis to reduce LVH. This antihypertrophic effect of bexarotene is independent of blood pressure.
Insights
RXR agonist bexarotene reduces pathological left ventricular hypertrophy in spontaneously hypertensive rats by activating the LKB1/AMPK pathway, independent of blood pressure changes.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pharmacology
Background:
- Retinoid X receptor (RXR) is crucial for cardiac development and implicated in cardiovascular diseases.
- Pathological left ventricular hypertrophy (LVH) is a significant concern in cardiovascular conditions.
Purpose of the Study:
- To investigate the effects of the RXRα agonist bexarotene on LVH in spontaneously hypertensive rats (SHR).
- To elucidate the underlying molecular mechanisms, focusing on the LKB1/AMPK signaling pathway.
Main Methods:
- SHRs were treated with bexarotene (30 or 100mg/kg) or vehicle for 12 weeks.
- Cardiac structure and function were assessed via echocardiography.
- In vitro studies used cardiomyocytes treated with Angiotensin II (AngII) and RXRα ligand 9-cis-RA to examine signaling pathway activation.
Main Results:
- Bexarotene significantly inhibited LVH in SHRs without lowering blood pressure.
- Bexarotene activated the LKB1/AMPK pathway and inhibited p70S6K in SHR heart tissue.
- AngII treatment reduced LKB1/AMPK activity and increased p70S6K activity in cardiomyocytes, effects antagonized by 9-cis-RA.
Conclusions:
- RXR agonists, like bexarotene, prevent LKB1/AMPK/p70S6K pathway inhibition and regulate protein synthesis to reduce LVH.
- The antihypertrophic effect of bexarotene is independent of its impact on blood pressure.
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