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Updated: Jun 6, 2025
Implantation of an Isoproterenol Mini-Pump to Induce Heart Failure in Mice
Published on: October 3, 2019
YAK577 Attenuates Cardiac Remodeling and Fibrosis in Isoproterenol-Infused Heart Failure Mice by Downregulating MMP12
Hongyan Zhou1,2, Hae Jin Kee1,3, Le Wan4
1Heart Research Center of Chonnam National University Hospital, Gwangju, Korea.
Insights
The novel histone deacetylase (HDAC) inhibitor YAK577 effectively treats heart failure by improving cardiac function and reducing fibrosis. It targets the HDAC8/matrix metalloproteinase 12 pathway, offering a new therapeutic approach for heart failure.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Heart failure is a critical condition with high mortality, often stemming from various cardiovascular diseases.
- Histone deacetylase (HDAC) inhibitors show promise in treating cardiac conditions but can cause side effects.
- Investigating novel HDAC inhibitors is crucial for developing safer and more effective heart failure treatments.
Purpose of the Study:
- To evaluate the efficacy of a novel HDAC inhibitor, YAK577, in a mouse model of heart failure.
- To elucidate the underlying molecular mechanisms of YAK577's action in heart failure.
- To assess YAK577's impact on cardiac hypertrophy, fibrosis, and left ventricular function.
Main Methods:
- YAK577 synthesized via methyl-2,3-diphenylpropanoate pathway.
- Heart failure induced using isoproterenol (ISO) in mice.
- Cardiac function assessed via echocardiography; hypertrophy and fibrosis quantified using specific markers and staining.
- HDAC8 and matrix metalloproteinase 12 (MMP12) expression analyzed through overexpression and knockdown studies.
Main Results:
- YAK577 treatment improved left ventricular ejection fraction and fractional shortening in ISO-induced heart failure.
- YAK577 significantly reduced cardiac hypertrophy markers and cardiomyocyte size.
- The compound ameliorated cardiac fibrosis and downregulated elevated HDAC8 and MMP12 levels.
- HDAC8 modulation directly impacted MMP12 and NPPB gene expression.
Conclusions:
- YAK577 demonstrates significant therapeutic potential for heart failure.
- The drug acts via the HDAC8/MMP12 signaling pathway.
- YAK577 represents a promising novel therapeutic agent for heart failure management.
Background And Objectives:
Heart failure is a potentially fatal event caused by diverse cardiovascular diseases, leading to high morbidity and mortality. Histone deacetylase (HDAC) inhibitors positively influence cardiac hypertrophy, fibrosis, hypertension, myocardial infarction, and heart failure, causing some side effects. We aimed to investigate the effect of the novel HDAC inhibitor YAK577 on the heart failure mouse model and its underlying mechanism.
Methods:
New hydroxamic acid YAK577 was prepared via methyl-2,3-diphenylpropanoate synthesis using carboxylic acids. We used a micro-osmotic pump, including isoproterenol (ISO; 80 mg/kg/day), to induce a heart failure with reduced ejection fraction. Cardiac hypertrophy was assessed by heart weight to body weight ratio and cross-sectional area. The left ventricular (LV) function was assessed by echocardiography. Fibrosis was evaluated using picrosirius red staining. Overexpression and knockdown experiments were performed to investigate the association between HDAC8 and matrix metalloproteinase 12 (MMP12).
Results:
YAK577 treatment restored ISO-induced reduction in LV fractional shortening and ejection fraction (n=9-11). YAK577 significantly downregulated cardiac hypertrophy marker genes (natriuretic peptide B, NPPB, and myosin heavy chain 7, MYH7) and cardiomyocyte size in vitro but not in vivo. YAK577 ameliorated cardiac fibrosis and fibrosis-related genes in vivo and in vitro. Additionally, YAK577 reduced elevated HDAC8 and MMP12 mRNA and protein expressions in ISO-infused mice, H9c2 cells, and rat neonatal cardiomyocytes. HDAC8 overexpression stimulated MMP12 and NPPB mRNA levels, while HDAC8 knockdown downregulated these genes.
Conclusions:
YAK577 acts as a novel heart failure drug through the HDAC8/MMP12 pathway.
