YAK577 Attenuates Cardiac Remodeling and Fibrosis in Isoproterenol-Infused Heart Failure Mice by Downregulating MMP12
- Author:
Hongyan ZHOU
1
;
Hae Jin KEE
;
Le WAN
;
Yodita ASFAHA
;
Fabian FISCHER
;
Matthias U KASSACK
;
Thomas KURZ
;
Seong Hoon KIM
;
Seung-Jung KEE
;
Young Joon HONG
;
Myung Ho JEONG
Author Information
- Publication Type:Original Research
- From:Korean Circulation Journal 2025;55(3):231-247
- CountryRepublic of Korea
- Language:English
-
Abstract:
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.
