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miR-154-5p Functions as an Important Regulator of Angiotensin II-Mediated Heart Remodeling
Que Wang1,2, Xiaoxue Yu1,2, Lin Dou2
1Peking University Fifth School of Clinical Medicine, Beijing 100730, China.
Insights
Increased miR-154-5p expression drives cardiac remodeling and cardiomyocyte damage caused by Angiotensin II (AngII). Inhibiting miR-154-5p or using telmisartan may offer therapeutic benefits for heart conditions.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- MicroRNA Research
Background:
- Cardiac remodeling, a pathological process driven by factors like hypertension and infarction, involves structural changes in the heart.
- Angiotensin II (AngII) is a key mediator in the development of cardiac remodeling.
- The specific role of microRNAs (miRNAs), such as miR-154-5p, in AngII-induced cardiac remodeling remains largely undefined.
Purpose of the Study:
- To investigate the function of miR-154-5p in AngII-induced cardiac remodeling.
- To elucidate the molecular mechanisms by which miR-154-5p contributes to cardiac remodeling.
- To assess the therapeutic potential of targeting miR-154-5p in cardiac remodeling.
Main Methods:
- Utilized adult C57BL/6J mice models treated with AngII to study cardiac remodeling.
- Employed miR-154-5p overexpression and inhibition strategies in vivo and in isolated cardiomyocytes.
- Investigated the direct interaction between miR-154-5p and its target gene, arylsulfatase B (Arsb), using 3'-UTR assays.
- Assessed the effect of telmisartan, an Angiotensin type 1 receptor blocker, on AngII-induced cardiac changes and miR-154-5p levels.
Main Results:
- AngII administration increased both miR-154-5p expression and cardiac remodeling markers in mice.
- Overexpression of miR-154-5p mimicked AngII effects, causing cardiomyocyte hypertrophy, apoptosis, oxidative stress, and inflammation.
- miR-154-5p directly targeted and inhibited arylsulfatase B (Arsb) expression.
- Telmisartan treatment reduced AngII-induced cardiac hypertrophy, apoptosis, and fibrosis by suppressing miR-154-5p upregulation.
Conclusions:
- Elevated cardiac miR-154-5p is both necessary and sufficient for AngII-induced cardiomyocyte hypertrophy and apoptosis.
- miR-154-5p acts as a critical pathological factor in cardiac remodeling.
- Targeting miR-154-5p presents a potential therapeutic strategy for managing cardiac remodeling and related heart conditions.
Abstract:
Chronic hypertension, valvular heart disease, and heart infarction cause cardiac remodeling and potentially lead to a series of pathological and structural changes in the left ventricular myocardium and a progressive decrease in heart function. Angiotensin II (AngII) plays a key role in the onset and development of cardiac remodeling. Many microRNAs (miRNAs), including miR-154-5p, may be involved in the development of cardiac remolding, but the underlying molecular mechanisms remain unclear. We aimed to characterize the function of miR-154-5p and reveal its mechanisms in cardiac remodeling induced by AngII. First, angiotensin II led to concurrent increases in miR-154-5p expression and cardiac remodeling in adult C57BL/6J mice. Second, overexpression of miR-154-5p to a level similar to that induced by AngII was sufficient to trigger cardiomyocyte hypertrophy and apoptosis, which is associated with profound activation of oxidative stress and inflammation. Treatment with a miR-154-5p inhibitor noticeably reversed these changes. Third, miR-154-5p directly inhibited arylsulfatase B (Arsb) expression by interacting with its 3'-UTR and promoted cardiomyocyte hypertrophy and apoptosis. Lastly, the angiotensin type 1 receptor blocker telmisartan attenuated AngII-induced cardiac hypertrophy, apoptosis, and fibrosis by blocking the increase in miR-154-5p expression. Moreover, upon miR-154-5p overexpression in isolated cardiomyocytes, the protective effect of telmisartan was partially abolished. Based on these results, increased cardiac miR-154-5p expression is both necessary and sufficient for AngII-induced cardiomyocyte hypertrophy and apoptosis, suggesting that the upregulation of miR-154-5p may be a crucial pathological factor and a potential therapeutic target for cardiac remodeling.
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