Related Experiment Video
Updated: May 7, 2026
Mouse Electroacupuncture Fixation Device Fabrication for Electroacupuncture Pretreatment in Diabetic Cardiomyopathy Mouse Model
Published on: April 18, 2025
Regulation of acetylation restores proteolytic function of diseased myocardium in mouse and human
Ding Wang1, Caiyun Fang, Nobel C Zong
1Department of Physiology, UCLA School of Medicine, Los Angeles, California 90095;
Insights
Histone deacetylase (HDAC) inhibitors boost cardiac proteasome function by increasing acetylation of proteasome subunits. This strategy shows promise for treating heart failure by restoring proteolytic capacity in diseased myocardium.
Area of Science:
- Biochemistry
- Cardiovascular Biology
- Molecular Medicine
Background:
- Proteasome complexes are crucial for protein homeostasis and cardiac function.
- Impaired proteasomal activity contributes to cardiovascular disease progression.
- Restoring myocardial proteolytic function is clinically significant.
Purpose of the Study:
- To investigate the regulation of cardiac proteasomal activity by acetylation.
- To explore the therapeutic potential of histone deacetylase (HDAC) inhibitors in enhancing proteasomal function in the heart.
Main Methods:
- Treatment of murine and human myocardium with HDAC inhibitors (SAHA, sodium valproate).
- Analysis of 20S proteasome subunit acetylation using LC-MS/MS.
- Assessment of proteolytic capacity in healthy, ischemia/reperfusion-injured, and failing hearts.
Main Results:
- HDAC inhibition increased 20S proteasome subunit acetylation in murine and human myocardium.
- This acetylation led to enhanced proteolytic capacity, restoring function in injured hearts.
- The study identified the cardiac 20S acetylome, revealing novel acetylation sites.
Conclusions:
- Cardiac proteasomal activity is regulated by acetylation.
- HDAC inhibitors represent a novel therapeutic strategy to rescue compromised proteolytic function in heart failure.
- Acetylation of specific lysine residues directly contributes to improved proteasome function.
Abstract:
Proteasome complexes play essential roles in maintaining cellular protein homeostasis and serve fundamental roles in cardiac function under normal and pathological conditions. A functional detriment in proteasomal activities has been recognized as a major contributor to the progression of cardiovascular diseases. Therefore, approaches to restore proteolytic function within the setting of the diseased myocardium would be of great clinical significance. In this study, we discovered that the cardiac proteasomal activity could be regulated by acetylation. Histone deacetylase (HDAC) inhibitors (suberoylanilide hydroxamic acid and sodium valproate) enhanced the acetylation of 20S proteasome subunits in the myocardium and led to an elevation of proteolytic capacity. This regulatory paradigm was present in both healthy and acutely ischemia/reperfusion (I/R) injured murine hearts, and HDAC inhibition in vitro restored proteolytic capacities to baseline sham levels in injured hearts. This mechanism of regulation was also viable in failing human myocardium. With 20S proteasomal complexes purified from murine myocardium treated with HDAC inhibitors in vivo, we confirmed that acetylation of 20S subunits directly, at least in part, presents a molecular explanation for the improvement in function. Furthermore, using high-resolution LC-MS/MS, we unraveled the first cardiac 20S acetylome, which identified the acetylation of nine N-termini and seven internal lysine residues. Acetylation on four lysine residues and four N-termini on cardiac proteasomes were novel discoveries of this study. In addition, the acetylation of five lysine residues was inducible via HDAC inhibition, which correlated with the enhancement of 20S proteasomal activity. Taken as a whole, our investigation unveiled a novel mechanism of proteasomal function regulation in vivo and established a new strategy for the potential rescue of compromised proteolytic function in the failing heart using HDAC inhibitors.
