Acylations in Cardiovascular Diseases: Advances and Perspectives

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Acylations in Cardiovascular Diseases: Advances and Perspectives

Cardiovascular diseases (CVD) are the leading cause of death and disability worldwide, affecting over 1.5 billion people according to the World Health Organization. For decades, researchers have focused on how “epigenetic” changes—chemical tags on DNA and proteins that control gene activity—drive heart and blood vessel health. Histone acetylation, a well-studied modification where an acetyl group is added to histone proteins, is known to activate genes critical for cardiac repair and remodeling. But new research suggests a broader family of modifications—short-chain lysine acylations—may play equally important roles in CVD.

What Are Short-Chain Lysine Acylations?

Acylations are chemical reactions that add short-chain fatty acid (SCFA) groups (like crotonyl, propionyl, or succinyl) to lysine amino acids on proteins. In 2011, scientists first identified eight types of these modifications on histones (proteins that package DNA) in human cells. Since then, studies have linked acylations to processes like stem cell development, reproduction, and brain function. Now, researchers are turning to their role in CVD.

Histone Crotonylation and Cardiac Hypertrophy

One of the most studied short-chain acylations is crotonylation, which uses the SCFA crotonate. Enzymes like p300 and GCN5 add crotonyl groups (“writers”), while class I HDACs and SIRT1-3 remove them (“erasers”). A key regulator is ECHS1 (short-chain enoyl-CoA hydratase), which breaks down crotonyl-CoA—the molecule needed for crotonylation.

A 2021 study in Circulation by Xiaoqiang Tang and colleagues at Sichuan University’s West China Second University Hospital revealed a direct link between ECHS1, crotonylation, and heart disease. The team found that ECHS1 deficiency—seen in children with mitochondrial encephalopathy and cardiac defects—increases histone crotonylation (specifically marks H3K18cr and H2BK12cr) in heart cells. This excess crotonylation recruits a transcription factor called NFATc3 to “fetal” genes (like B-type natriuretic peptide), which reactivate in diseased hearts and drive cardiac hypertrophy (enlarged heart muscle).

Notably, this mechanism differs from histone acetylation: while acetylation often protects the heart, inhibiting crotonylation could treat ECHS1-related hypertrophy. This is a critical distinction—offering a new therapeutic target for patients with rare genetic heart conditions.

Beyond Crotonylation: Propionylation, Succinylation, and Malonylation

Crotonylation is just one piece of the puzzle. Other acylations are emerging as key players in CVD:

  • Propionylation: Adding a propionyl group to proteins. In platelets, propionylation of tropomodulin-3 increases thrombosis risk in mice (Circulation, 2020). Even non-histone proteins matter—propionylation of manganese superoxide dismutase 2 (a antioxidant enzyme) drives oxidative stress, a major CVD risk factor.
  • Succinylation: A modification regulated by SIRT5, a mitochondrial enzyme. PNAS research (2016) found that SIRT5’s ability to remove succinyl groups from mitochondrial proteins is essential for heart function—mice lacking SIRT5 die young from cardiac failure.
  • Malonylation: Adds a malonyl group. This modification impairs mTORC1, a protein kinase critical for blood vessel growth. In Cell Metabolism (2018), scientists showed malonylation leads to angiogenic defects—linked to heart attacks where new blood vessels fail to form.

Open Questions and Future Directions

While these findings are promising, much remains unknown:

  • Vascular biology: Do short-chain acylations affect blood pressure or atherosclerosis, key CVD drivers?
  • Acylation crosstalk: How do crotonylation, acetylation, and propionylation interact to regulate gene activity?
  • Gut-heart link: SCFAs are made by gut bacteria—could microbiota changes drive CVD via acylations?
  • Non-histone targets: Most studies focus on histones, but non-histone proteins (like enzymes or signaling molecules) may be equally important.

Conclusion

Short-chain lysine acylations represent a new frontier in CVD research. From crotonylation driving cardiac hypertrophy to succinylation maintaining mitochondrial health, these modifications connect metabolism (how cells make energy) to gene activity—a critical link in heart disease. For patients with ECHS1 mutations or treatment-resistant hypertrophy, inhibiting crotonylation could offer hope. For the broader CVD community, this work reminds us: epigenetic regulation is more complex—and more promising—than we ever thought.

Original Study and References

This perspective is based on research by Xiaofeng Chen, Cechuan Deng, Han Wang, and Xiaoqiang Tang from Sichuan University’s West China Second University Hospital and Chengdu University of Traditional Chinese Medicine. The study was funded by the National Natural Science Foundation of China (81970426, 81800273, 82004097), the Young Elite Scientists Sponsorship Program of the China Association for Science and Technology (2018QNRC001), and the Sichuan Province Scientific and Technological Innovation Talents Program (2020JDRC0017).

Key references include:

  • Tang X, et al. Short-chain enoyl-CoA hydratase mediates histone crotonylation and contributes to cardiac homeostasis. Circulation 2021;143:1066–1069.
  • Li P, et al. Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease. Nat Rev Cardiol 2020;17:96–115.
  • Sadhukhan S, et al. Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function. Proc Natl Acad Sci U S A 2016;113:4320–4325.

doi:10.1097/CM9.0000000000001941

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