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Updated: Dec 10, 2025
Author Spotlight: Improved Localization and Monitoring of Coronary Flow Reserve Using Modified PLAX View in Mice
Published on: August 25, 2023
Histone Acetyltransferase p300 Inhibitor Improves Coronary Flow Reserve in SIRT3 (Sirtuin 3) Knockout Mice
Han Su1,2, Heng Zeng1, Xiaochen He1
1Department of Pharmacology and Toxicology University of Mississippi Medical Center Jackson MS.
Insights
Histone acetyltransferase p300 inhibitor C646 improved coronary flow reserve (CFR) and cardiac function in Sirtuin 3 knockout mice. C646 treatment reversed cardiac remodeling and endothelial cell dysfunction by reducing p300 acetylation and NF-κB signaling.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Mitochondrial Biology
Background:
- Coronary microvascular dysfunction is prevalent in myocardial infarction with non-obstructive coronary artery disease.
- Coronary flow reserve (CFR) is a key indicator of microvascular function and heart failure.
- Sirtuin 3 (SIRT3) deficiency impairs CFR and diastolic function, with limited therapeutic options.
Purpose of the Study:
- To investigate the therapeutic potential of C646, a p300 inhibitor, on CFR and cardiac remodeling in SIRT3 knockout (SIRT3KO) mice.
- To elucidate the molecular mechanisms underlying C646's effects in the context of SIRT3 deficiency.
Main Methods:
- SIRT3KO mice were treated with C646 for 14 days.
- Assessment of CFR, arterial stiffness (pulse-wave velocity), and cardiac function (ejection fraction, fractional shortening).
- Histological analysis for cardiac fibrosis, hypertrophy, and capillary density; molecular analysis of p300, H3K56 acetylation, endothelial nitric oxide synthase, arginase II, NF-κB, and VCAM-1.
Main Results:
- C646 treatment significantly improved CFR, pulse-wave velocity, ejection fraction, and fractional shortening in SIRT3KO mice.
- C646 reversed cardiac fibrosis, hypertrophy, and capillary rarefaction.
- Mechanistically, C646 reduced p300 and H3K56 acetylation, increased endothelial nitric oxide synthase, decreased arginase II, and suppressed NF-κB and VCAM-1 expression.
Conclusions:
- C646 effectively attenuates p300 and H3K56 acetylation in SIRT3-deficient hearts.
- C646 improves arterial stiffness and CFR by enhancing endothelial cell function and inhibiting NF-κB signaling.
- C646 demonstrates therapeutic promise for conditions characterized by coronary microvascular dysfunction and heart failure.
Abstract:
Background Coronary microvascular dysfunction is common in patients of myocardial infarction with non-obstructive coronary artery disease. Coronary flow reserve (CFR) reflects coronary microvascular function and is a powerful independent index of coronary microvascular dysfunction and heart failure. Our previous studies showed that knockout of SIRT3 (Sirtuin 3) decreased CFR and caused a diastolic dysfunction. Few studies focus on the treatment of impaired CFR and heart failure. In the present study, we explored the role of C646, a histone acetyltransferase p300 inhibitor, in regulating CFR and cardiac remodeling in SIRT3 knockout (SIRT3KO) mice. Methods and Results After treating with C646 for 14 days, CFR, pulse-wave velocity, and cardiac function were measured in SIRT3KO mice. SIRT3KO mice treated with C646 showed a significant improvement of CFR, pulse-wave velocity, ejection fraction, and fractional shortening. Treatment with C646 reversed pre-existing cardiac fibrosis, hypertrophy, and capillary rarefaction in SIRT3KO mice. Mechanistically, knockout of Sirtuin 3 resulted in significant increases in p300 expression and H3K56 acetylation. Treatment with C646 significantly reduced levels of p300 and H3K56 acetylation in SIRT3KO mice. Furthermore, treatment with C646 increased endothelial nitric oxide synthase expression and reduced arginase II expression and activity. The expression of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and VCAM-1 (vascular cell adhesion molecule 1) was also significantly suppressed by C646 treatment in SIRT3KO mice. Conclusions C646 treatment attenuated p300 and H3K56 acetylation and improved arterial stiffness and CFR via improvement of endothelial cell (EC) dysfunction and suppression of NF-κB.
