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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
HBI-8000 improves heart failure with preserved ejection fraction via the TGF-β1/MAPK signalling pathway
Jing Tian1, Wenjing Li1, Lu Zeng2
1Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Insights
Chidamide (HBI-8000) shows promise for treating heart failure with preserved ejection fraction (HFpEF). This study found HBI-8000 inhibits cardiac fibrosis and hypertrophy by modulating the TGF-β1/MAPK pathway, offering new hope for HFpEF patients.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Heart failure with preserved ejection fraction (HFpEF) affects 50% of heart failure patients, presenting with cardiac remodeling and comorbidities.
- Limited effective treatment options exist for HFpEF, highlighting the need for novel therapeutic strategies.
- Chidamide (HBI-8000), a histone deacetylase inhibitor, is approved for T-cell lymphomas but shows potential in cardiovascular disease.
Purpose of the Study:
- To investigate the therapeutic potential of Chidamide (HBI-8000) in treating heart failure with preserved ejection fraction (HFpEF).
- To elucidate the cellular mechanisms by which HBI-8000 impacts myocardial fibrosis and hypertrophy in HFpEF models.
Main Methods:
- In vivo studies utilizing HFpEF models.
- Cellular assays examining the effects of HBI-8000 on cardiac fibroblasts (CFs) and the TGF-β1/MAPK pathway.
- Analysis of fibrosis-related factors and phosphorylated MAPKs (p38MAPK, JNK, ERK).
Main Results:
- HBI-8000 inhibited AngII-induced proliferation and activation of cardiac fibroblasts.
- HBI-8000 downregulated fibrosis-related factors and significantly reduced TGF-β1 and phosphorylated MAPK expression in HFpEF models.
- The drug's effects were linked to the modulation of the TGF-β1/MAPK pathway, a key driver of fibrotic remodeling.
Conclusions:
- Chidamide (HBI-8000) demonstrates efficacy in inhibiting myocardial fibrosis and hypertrophy in HFpEF.
- Modulation of the TGF-β1/MAPK pathway is the underlying mechanism for HBI-8000's therapeutic effects in HFpEF.
- HBI-8000 represents a potential novel therapeutic agent for patients with heart failure with preserved ejection fraction.
Abstract:
Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of total heart failure patients and is characterized by peripheral circulation, cardiac remodelling and comorbidities (such as advanced age, obesity, hypertension and diabetes) with limited treatment options. Chidamide (HBI-8000) is a domestically produced benzamide-based histone deacetylase isoform-selective inhibitor used for the treatment of relapsed refractory peripheral T-cell lymphomas. Based on our in vivo studies, we propose that HBI-8000 exerts its therapeutic effects by inhibiting myocardial fibrosis and myocardial hypertrophy in HFpEF patients. At the cellular level, we found that HBI-8000 inhibits AngII-induced proliferation and activation of CFs and downregulates the expression of fibrosis-related factors. In addition, we observed that the HFpEF group and AngII stimulation significantly increased the expression of TGF-β1 as well as phosphorylated p38MAPK, JNK and ERK, whereas the expression of the above factors was significantly reduced after HBI-8000 treatment. Activation of the TGF-β1/MAPK pathway promotes the development of fibrotic remodelling, and pretreatment with SB203580 (p38MAPK inhibitor) reverses this pathological change. In conclusion, our data suggest that HBI-8000 inhibits fibrosis by modulating the TGF-β1/MAPK pathway thereby improving HFpEF. Therefore, HBI-8000 may become a new hope for the treatment of HFpEF patients.
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