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Updated: Aug 29, 2026
Studying Left Ventricular Reverse Remodeling by Aortic Debanding in Rodents
Published on: July 14, 2021
Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling
Osamu Yamaguchi1, Yoshiharu Higuchi, Shinichi Hirotani
1Departments of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Insights
Apoptosis signal-regulating kinase 1 (ASK1) promotes left ventricular remodeling after heart injury. Inhibiting ASK1 reduces cardiac cell death and improves heart function, offering a potential therapeutic target for heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Signaling
Background:
- Left ventricular remodeling post-myocardial infarction (MI) and pressure overload is a key factor in heart failure progression.
- The precise molecular mechanisms driving this remodeling process remain incompletely understood.
- Apoptosis signal-regulating kinase 1 (ASK1), a stress-induced apoptosis mediator, is implicated in cellular stress responses.
Purpose of the Study:
- To investigate the role of ASK1 in the development of left ventricular remodeling following cardiac injury.
- To determine if ASK1 deficiency mitigates adverse cardiac remodeling and dysfunction.
Main Methods:
- Utilized ASK1 knockout (ASK-/-) mice and wild-type (WT) littermates.
- Induced myocardial infarction via coronary artery ligation and pressure overload via thoracic transverse aortic constriction (TAC).
- Assessed cardiac structure and function using echocardiography and cardiac catheterization; evaluated myocyte apoptosis via TUNEL staining; confirmed ASK1 activity and apoptosis induction in vitro.
Main Results:
- ASK-/- mice exhibited significantly attenuated left ventricular dilation and preserved fractional shortening compared to WT mice after MI and TAC.
- A marked reduction in apoptotic myocytes (TUNEL-positive) was observed in ASK-/- hearts post-injury.
- Overexpression of active ASK1 induced apoptosis in cardiomyocytes, while ASK-/- cardiomyocytes showed resistance to H2O2-induced apoptosis.
Conclusions:
- ASK1 plays a critical role in mediating left ventricular remodeling and dysfunction after cardiac injury.
- ASK1 promotes apoptosis in cardiomyocytes, contributing to adverse remodeling.
- Targeting ASK1 may represent a novel therapeutic strategy for preventing or treating heart failure post-MI and pressure overload.
Abstract:
Left ventricular remodeling that occurs after myocardial infarction (MI) and pressure overload is generally accepted as a determinant of the clinical course of heart failure. The molecular mechanism of this process, however, remains to be elucidated. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We used ASK1 knockout mice (ASK-/-) to test the hypothesis that ASK1 is involved in development of left ventricular remodeling. ASK-/- hearts showed no morphological or histological defects. Echocardiography and cardiac catheterization revealed normal global structure and function. Left ventricular structural and functional remodeling were determined 4 weeks after coronary artery ligation or thoracic transverse aortic constriction (TAC). ASK-/- had significantly smaller increases in left ventricular end-diastolic and end-systolic ventricular dimensions and smaller decreases in fractional shortening in both experimental models compared with WT mice. The number of terminal deoxynucleotidyl transferase biotin-dUDP nick end-labeling-positive myocytes after MI or TAC was decreased in ASK-/- compared with that in WT mice. Overexpression of a constitutively active mutant of ASK1 induced apoptosis in isolated rat neonatal cardiomyocytes, whereas neonatal ASK-/- cardiomyocytes were resistant to H2O2-induced apoptosis. An in vitro kinase assay showed increased ASK1 activity in heart after MI or TAC in WT mice. Thus, ASK1 plays an important role in regulating left ventricular remodeling by promoting apoptosis.
