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Published on: June 14, 2016
Lenalidomide attenuates cardiac fibrosis and inflammation induced by β-adrenergic receptor activation
Ran Jiao1, Wenqi Li2, Xiaoting Gu1
1State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin 300353, China; Tianjin Key Laboratory of Molecular Drug Research, International Joint Academy of Biomedicine, Tianjin 300457, China.
Insights
Lenalidomide (Len) alleviates cardiac fibrosis and inflammation caused by excessive beta-adrenergic receptor (β-AR) activation. This drug targets AKT1, impacting PI3K/AKT, ERK, and NF-κB signaling pathways.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Excessive beta-adrenergic receptor (β-AR) activation is implicated in cardiovascular diseases, leading to cardiac fibrosis and inflammation.
- Lenalidomide (Len) demonstrates anti-fibrotic properties in various conditions, but its role in β-AR-mediated cardiac issues is not fully understood.
Purpose of the Study:
- To investigate the efficacy of Lenalidomide (Len) in mitigating cardiac fibrosis and inflammation induced by β-AR overactivation.
- To elucidate the underlying molecular mechanisms, including signaling pathways and potential molecular targets.
Main Methods:
- Mice were treated with isoproterenol (ISO) to induce β-AR overactivation, with or without Lenalidomide (Len) pretreatment.
- Cardiac function, fibrosis, and inflammation were assessed in vivo.
- Cardiac fibroblasts and macrophages were treated in vitro to examine Len's effects on cellular activation and inflammatory responses.
- Signaling pathways (PI3K/AKT, ERK, NF-κB) and gene expression were analyzed.
- KEGG enrichment analysis was performed to identify molecular targets.
Main Results:
- Lenalidomide (Len) alleviated β-AR-induced cardiac dysfunction and fibrosis in vivo, mediated by PI3K/AKT and ERK signaling.
- Len attenuated β-AR-induced cardiac fibroblast activation via PI3K/AKT and ERK pathways in vitro.
- Len suppressed β-AR-induced cardiac inflammation and macrophage pro-inflammatory cytokine expression in vivo and in vitro, involving PI3K/AKT and NF-κB signaling.
- KEGG analysis identified AKT1 as a key target of Len in both cardiac fibroblasts and macrophages.
Conclusions:
- Lenalidomide (Len) effectively ameliorates cardiac fibrosis and inflammation resulting from β-adrenergic insult.
- The protective mechanisms of Len involve modulation of PI3K/AKT, ERK, and NF-κB signaling pathways.
- Len exerts its therapeutic effects by targeting AKT1 in cardiac cells and macrophages.
Abstract:
β-Adrenergic receptor (β-AR) excessive activation assumes a vital role in various cardiovascular diseases and mediates cardiac fibrosis and cardiac inflammation. Lenalidomide (Len) has shown anti-fibrosis effects in diverse fibrotic diseases. However, it is unclear whether and how Len suppresses cardiac fibrosis and cardiac inflammation triggered by β-AR overactivation. In our research, mice were treated in the presence of or in the absence of the β-AR agonist isoproterenol (ISO) and with or without Len pretreatment. Interestingly, the results showed that Len alleviated β-AR-induced cardiac dysfunction and cardiac fibrosis by PI3K/AKT and ERK signalings in vivo. Consistently, Len also attenuated β-AR-induced cardiac fibroblasts activation by PI3K/AKT and ERK signalings in vitro. Besides, Len suppressed β-AR-induced cardiac inflammation by PI3K/AKT and NF-κB signalings in vivo. Similarly, Len inhibited β-AR-induced macrophages pro-inflammatory cytokines expression by PI3K/AKT and NF-κB signalings in vitro. To further explore the protective mechanism of Len, we used KEGG enrich analysis and found that Len functioned in therapeutic effects by targeting AKT1 in both cardiac fibroblasts and macrophages. In summary, our study demonstrated that Len ameliorated cardiac fibrosis and cardiac inflammation upon β-adrenergic insult. And the mechanism suggested that Len function in cardiac fibrosis and inflammation via targeting AKT1.
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