Acylations in Cardiovascular Diseases: Advances and Perspectives

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Acylations in Cardiovascular Diseases: Advances and Perspectives

Cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality globally. Over the past two decades, extensive research has focused on the role of epigenetic modifications, particularly histone acetylation and methylation, in regulating cardiovascular development, homeostasis, and disease progression. These modifications influence gene transcription and have been implicated in pathological processes such as cardiac hypertrophy, heart failure, and diabetic cardiomyopathy. While histone acetylations like H3K9ac and H3K27ac are well-characterized activators of transcription, recent studies have expanded the scope of post-translational modifications to include diverse short-chain lysine acylations. These emerging modifications—such as crotonylation, propionylation, succinylation, and malonylation—are now recognized as critical regulators of cardiovascular health and disease.

Histone Acetylation and Cardiovascular Homeostasis

Histone acetylation, catalyzed by histone acetyltransferases (HATs), facilitates chromatin relaxation and transcriptional activation. Conversely, histone deacetylases (HDACs) remove acetyl groups, promoting chromatin condensation and gene silencing. Class I and II HDACs are generally associated with pathological cardiac remodeling, while class III HDACs (Sirtuins) exhibit cardioprotective effects. For example, inhibitors of class I HDACs have shown therapeutic potential in attenuating cardiac hypertrophy and heart failure. However, the roles of non-acetyl acylations in cardiovascular biology remained obscure until recent advances linked these modifications to metabolic regulation and disease mechanisms.

Short-Chain Fatty Acids and Lysine Acylations

Short-chain fatty acids (SCFAs), including succinate, propionate, butyrate, and crotonate, are derived from gut microbiota and cellular metabolism. These metabolites serve as substrates for lysine acylations, which modify histones and non-histone proteins to regulate cellular functions. In 2011, a landmark study identified eight types of short-chain lysine acylations in mammalian cells, revealing their widespread influence on gene expression and metabolic pathways. Among these, histone crotonylation has emerged as a key player in cardiovascular pathophysiology.

Histone Crotonylation in Cardiac Hypertrophy

Histone crotonylation, characterized by the addition of a crotonyl group to lysine residues, is dynamically regulated by writers (e.g., p300 and GCN5), erasers (e.g., class I HDACs and SIRT1-3), and metabolic enzymes like short-chain enoyl-CoA hydratase (SCEH/ECHS1). Clinically, mutations in ECHS1 are linked to hypertrophic and dilated cardiomyopathy. ECHS1 deficiency elevates intracellular crotonyl-CoA levels, leading to hyper-crotonylation of histones (e.g., H3K18cr and H2BK12cr) and activation of fetal genes such as B-type natriuretic peptide (BNP). This aberrant gene expression drives pathological cardiac hypertrophy by facilitating the recruitment of transcription factors like nuclear factor of activated T-cells C3 (NFATc3) to promoters of pro-hypertrophic genes.

Mechanistically, mitochondrial fatty acid β-oxidation influences crotonyl-CoA availability, directly coupling metabolic flux to epigenetic regulation. Inhibiting histone crotonylation may thus offer therapeutic benefits for patients with ECHS1 mutations or acquired forms of cardiac hypertrophy.

Propionylation, Succinylation, and Malonylation in Cardiovascular Biology

Beyond crotonylation, other short-chain acylations contribute to cardiovascular homeostasis:

  1. Propionylation: Histone propionylation (e.g., H3K14pr and H3K23pr) is catalyzed by the BRPF1–KAT6 complex. Deficiencies in these modifications are associated with congenital heart defects. Non-histone propionylation also plays roles in thrombosis and oxidative stress. For instance, tropomodulin-3 propionylation in platelets enhances thrombosis risk, while propionate-induced propionylation of manganese superoxide dismutase 2 (SOD2) exacerbates oxidative damage.

  2. Succinylation: Mitochondrial succinylation, regulated by the desuccinylase SIRT5, is critical for cardiac function. SIRT5-deficient mice exhibit impaired desuccinylation of metabolic enzymes, leading to mitochondrial dysfunction and early mortality. Succinylation also modulates energy metabolism, impacting conditions like ischemic injury and heart failure.

  3. Malonylation: Malonylation inhibits mechanistic target of rapamycin complex 1 (mTORC1) activity, disrupting angiogenesis and exacerbating post-ischemic tissue damage. This modification is implicated in diabetic complications, where malonylation of glycolytic enzymes alters substrate utilization and promotes endothelial dysfunction.

Metabolic Regulation of Acylations

Lysine acylations are tightly coupled to cellular metabolism. Enzymes such as acetyl-CoA synthetase 2 (ACSS2) and ATP citrate lyase (ACLY) generate acyl-CoA donors from metabolites, linking nutrient availability to epigenetic states. For example:

  • Crotonyl-CoA: Derived from fatty acid β-oxidation and amino acid catabolism, crotonyl-CoA levels dictate the extent of histone crotonylation.
  • Propionyl-CoA and Succinyl-CoA: These metabolites originate from gut microbiota-derived SCFAs and the tricarboxylic acid (TCA) cycle, respectively, influencing propionylation and succinylation.
  • Malonyl-CoA: Produced during fatty acid synthesis, malonyl-CoA regulates both lipid metabolism and protein malonylation.

Figure 1 in the original study illustrates how acyl-CoAs bridge metabolic pathways to histone and non-histone acylation, modulating gene transcription and signaling cascades in CVD.

Therapeutic Implications and Future Directions

The discovery of short-chain acylations has opened new avenues for CVD treatment. Key unresolved questions and research priorities include:

  1. Mechanistic Insights: Elucidating the roles of specific acylations (e.g., crotonylation vs. propionylation) in distinct cardiovascular pathologies, such as myocardial infarction, hypertension, and diabetic cardiomyopathy. Chromatin immunoprecipitation sequencing (ChIP-seq) and assay for transposase-accessible chromatin sequencing (ATAC-seq) could map acylation-dependent chromatin remodeling events.

  2. Crosstalk Between Acylations: Investigating spatial and temporal interactions between different modifications. For instance, competitive or cooperative dynamics between acetylation and crotonylation may fine-tune metabolic gene expression during stress responses.

  3. Gut Microbiota and Systemic Signaling: Exploring how gut microbiota-derived SCFAs influence cardiovascular health via acylations. Propionate and butyrate may modulate insulin signaling, AMP-activated protein kinase (AMPK), and FOXO transcription factors, linking intestinal metabolism to cardiac and vascular function.

  4. Targeted Therapies: Developing inhibitors or activators of acyltransferases, deacylases, and metabolic enzymes to modulate acylation levels. For example, ECHS1 activators or crotonyl-CoA hydratase inhibitors could mitigate pathological histone crotonylation in hypertrophy.

  5. Non-Histone Targets: Expanding research beyond histones to identify acylation-dependent regulation of signaling proteins. For example, mTORC1 malonylation and SOD2 propionylation highlight the broad impact of these modifications on cellular homeostasis.

Conclusion

The landscape of lysine acylations in cardiovascular biology has evolved from a narrow focus on acetylation to a broader appreciation of diverse short-chain modifications. Crotonylation, propionylation, succinylation, and malonylation are now recognized as pivotal regulators of gene expression, metabolic flux, and cellular signaling in CVD. These modifications integrate environmental cues—such as gut microbiota metabolites and mitochondrial energetics—with epigenetic and non-epigenetic mechanisms to influence disease progression. Future studies must address the complexity of acylation crosstalk, organ-specific effects, and therapeutic targeting to translate these discoveries into clinical interventions. By unraveling the “acylome” in cardiovascular health, researchers may uncover novel strategies to combat the global burden of heart disease.

doi.org/10.1097/CM9.0000000000001941

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