Targeting Histone Modifications In Atherosclerosis and Coronary Artery Disease

Abstract

In recent years, there has been growing interest in the epigenetic mechanisms underlying cardiovascular diseases, particularly atherosclerosis and coronary artery disease (AS and CAD). Emerging evidence suggests that histone modification plays a pivotal role in the pathogenesis of AS and CAD by modulating key processes such as vascular inflammation, endothelial dysfunction, and plaque stability. Recent studies have reported the potential of histone deacetylase (HDAC) inhibitors as targeted therapies for AS/CAD. By inhibiting HDAC activity, they maintain histone acetylation, which can reduce inflammation, promote endothelial repair, and prevent vascular smooth muscle cell proliferation. With a focus on precision medicine, we examine how these inhibitors can be integrated into innovative drug delivery systems, offering a promising avenue for enhancing therapeutic efficacy and minimizing adverse effects. This approach not only represents a novel strategy in managing AS/CAD but also highlights the broader implications of epigenetic interventions in cardiovascular medicine. This paper discusses the pathology of AS/CAD and the role of histone modifications, specifically histone acetylation, in these conditions. Additionally, this paper will discuss new drug delivery systems that improve target specificity and reduce off-target effects. Ultimately, this review concludes that HDAC inhibitors, when combined with advanced drug delivery systems, hold significant promise for reducing vascular inflammation and enhancing patient outcomes in AS/CAD treatment.

Introduction

Heart disease remains one of the leading causes of death worldwide. According to the World Health Organization (WHO), cardiovascular diseases (CVDs) were responsible for approximately 17.9 million deaths in 2019, accounting for 32% of all global deaths (WHO, 2021). In the United States, the American Heart Association (AHA) reported that nearly 697,000 people died from heart disease in 2020, representing one in every five deaths (AHA, 2023). These statistics underscore the profound impact of heart disease on global and national health systems. There are several types of heart disease, with Atherosclerosis and Coronary Artery Disease being the most common and critical contributors to these statistics.

Atherosclerosis is characterized by the buildup of fatty deposits, including cholesterol and other lipids, within the arterial walls. This accumulation leads to the formation of plaques that narrow and stiffen the arteries, thereby impeding blood flow (Libby, 2021). Atherosclerosis affects the coronary arteries, the vessels supplying blood to the heart muscle, and leads to coronary artery disease. CAD is the leading cause of heart disease and is associated with severe cardiovascular events such as angina, myocardial infarction, and stroke (Ross, 1999). Due to the significant morbidity and mortality associated with AS and CAD, these conditions have become a central focus of cardiovascular research. The growing urgency to address these life-threatening diseases has motivated extensive investigation into their underlying mechanisms, with particular attention given to the role of inflammation, endothelial dysfunction, and plaque stability in their progression. This drive to better understand AS/CAD has also led to the exploration of novel therapeutic strategies, including the modulation of epigenetic factors such as histone modifications.

Research into the pathology of AS/CAD has deepened our understanding and led to the discovery of novel therapies that have mitigated the disease's effects and improved patient outcomes (Lusis et al., 2004). However, the complex nature of AS/CAD requires ongoing investigation to advance therapies and improve disease management.

Studies have identified key genetic factors that contribute to the pathology of AS/CAD. For example, variants in genes related to lipid metabolism, such as APOE and PCSK9, significantly impact the risk of developing these conditions (Khera et al., 2016; Kathiresan et al., 2017). By understanding these genetic influences and the gene networks involved in heart function and AS/CAD pathology, researchers can uncover novel therapeutic approaches that target the underlying molecular mechanisms, offering new ways to address the complex pathophysiology of these diseases. Beyond traditional genetic modifications, some research has focused on epigenetic factors that influence gene expression without altering the underlying DNA sequence. Epigenetic modifications, such as DNA methylation and histone modifications, regulate key genes involved in AS/CAD and offer intriguing possibilities for therapeutic intervention (Zaina et al., 2015; Kouzarides, 2007). In particular, histone modifications, including acetylation and methylation, play a crucial role in regulating genes involved in AS/CAD, offering new possibilities for therapeutic intervention (Strahl & Allis, 2000).

Among these, histone modifications, particularly acetylation, have gained significant attention due to their extensive study and established role in disease progression. Histone acetylation has been widely researched in human diseases such as cancer, where it can modulate gene expression to influence tumor behavior and treatment responses. Studies have demonstrated that enhancing histone acetylation can improve therapeutic outcomes by promoting the expression of genes that inhibit tumor growth, all while maintaining a favorable safety profile with minimal toxicity (Gao et al., 2021).This positions histone acetylation as a promising therapeutic target in AS/CAD, where altered acetylation patterns contribute to key pathological mechanisms, including vascular inflammation, endothelial dysfunction, and plaque instability.

Histone acetylation involves adding acetyl groups to lysine residues, which generally promotes gene activation by making chromatin more accessible (Ruthenburg et al., 2020). Next, histone methylation adds methyl groups to lysine or arginine residues, influencing gene expression depending on the specific residues modified (Klose & Zhang, 2016). Changes in histone modifications significantly impact the expression of genes crucial to the development and progression of atherosclerosis and coronary artery disease (AS/CAD). Specifically, altered histone acetylation patterns have been associated with genes involved in key pathological mechanisms, including vascular inflammation, endothelial dysfunction, and plaque stability. Alternatively, increased histone acetylation has been linked to enhanced expression of inflammatory cytokines and endothelial cell dysfunction, both of which contribute to disease progression (Gao et al., 2021; Marfella et al., 2022). Additionally, aberrant acetylation patterns are associated with impaired plaque stability, further complicating disease management (Zhang et al., 2021). This review details the pathogenesis of atherosclerosis and coronary artery disease (AS/CAD), the role of epigenetics in disease progression, and the potential for histone deacetylase (HDAC) inhibition to ameliorate AS/CAD. We examine the mechanisms of histone acetylation, the specificity of HDAC inhibitors, and innovative delivery methods, highlighting how these factors collectively enhance the efficacy of precision medicine in treating AS/CAD. By understanding these elements, we can better assess the potential future impact of tailored therapeutic strategies on improving patient outcomes in cardiovascular disease.

Atherosclerosis: A State of Vascular Dysfunction

Figure 1 (Progression of Atherosclerotic Plaques)

Figure 1 illustrates the stages of plaque formation within the arterial wall beginning with endothelial dysfunction and the subsequent recruitment of inflammatory cells. As inflammation progresses, smooth muscle cells (SMCs) migrate into the intima, contributing to the formation of a fibrous cap over the plaque. Over time, the plaque stabilizes; however, ongoing inflammation can weaken the cap, leading to potential plaque rupture. These plaques, formed from lipids and inflammatory cells, lead to vessel stenosis and subsequent ischemic events, such as heart attacks and strokes (Libby et al., 2019). Given that coronary artery disease (CAD) is a significant consequence of advanced atherosclerosis, understanding these stages is crucial for developing targeted therapies aimed at mitigating plaque instability and reducing the risk of severe cardiovascular events.

As the plaques mature, smooth muscle cells (SMCs) migrate into the arterial intima, stabilizing the plaques by synthesizing extracellular matrix (ECM) components (Otsuka et al., 2014). However, as AS progresses to CAD, the fibrous cap overlying the lipid-rich core of the plaque can thin and weaken due to ongoing inflammation, leading to a risk of plaque rupture and subsequent thrombotic events (Libby et al., 2019). Smooth muscle cells (SMCs) play a central role in maintaining plaque stability through the production of extracellular matrix (ECM). However, in response to stimuli such as oxidized LDL cholesterol and pro-inflammatory cytokines, SMCs undergo a phenotypic switch from a contractile to a synthetic state (Murray, 2019). This shift increases ECM production but when coupled with inflammation, destabilizes the plaques. Therefore, understanding these processes is crucial for developing therapeutic strategies aimed at preventing plaque rupture and reducing the risk of acute cardiovascular events.

Genetic Factors Contributing to Atherosclerosis and Coronary Artery Disease

While environmental factors such as diet and lifestyle undeniably influence disease development, genetic predisposition is increasingly recognized as a major factor in both the initiation and progression of AS and CAD. Genetic variations, such as those affecting lipid metabolism, inflammatory responses, and endothelial function; can significantly increase an individual's susceptibility to these diseases, even in the presence of favorable environmental conditions (Goldstein & Brown, 2015).

Among the various genes implicated in AS and CAD, Apolipoprotein E (APOE), which is involved in lipid metabolism and vascular inflammation, is one of the most studied. The APOE gene exists in three major alleles: APOE2, APOE3, and APOE4. The APOE4 allele, in particular, is associated with an increased risk for AS and CAD due to a single nucleotide polymorphism (SNP) that results in an arginine-to-cysteine substitution at position 112 (Cohen et al., 2017). This mutation impairs lipid binding and metabolism, leading to cholesterol accumulation in arterial walls and promoting plaque formation (Mahley, 2016; Liu et al., 2023). Carriers of the APOE4 allele exhibit higher levels of cholesterol-rich lipoproteins and heightened inflammation, contributing to the vulnerability and progression of plaques. Gene editing techniques like CRISPR-Cas9, which hold the potential for modulating APOE expression (Bennet et al., 2020). Additionally, epigenetic mechanisms influencing APOE expression, such as histone modifications, offer further therapeutic possibilities (Li et al., 2022).

Role of Histone Modifications in Atherosclerosis and Coronary Artery Disease

Figure 2: Chromatin remodelling complexes in the dynamic regulation of transcription

Figure 2 illustrates how chromatin remodeling complexes function to control the accessibility of chromatin, thereby regulating gene transcription. Chromatin exists in two primary states: a condensed form (heterochromatin), which is transcriptionally inactive, and a relaxed form (euchromatin), which is accessible to transcription machinery.

Histones, which package DNA into chromatin, undergo various modifications, such as acetylation, methylation, and phosphorylation. These modifications can alter chromatin structure, leading to changes in gene expression. For instance, histone acetylation, which is the focus of this section, generally leads to chromatin relaxation, facilitating transcriptional activation, whereas deacetylation compacts chromatin; leading to gene repression (Zaina et al., 2015).

The balance of histone acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Aberrant regulation of these enzymes has been implicated in cardiovascular diseases, particularly AS and CAD. Dysregulated histone acetylation has been shown to affect the expression of genes involved in critical processes such as vascular inflammation, lipid metabolism, and plaque stability. For example, increased histone acetylation in inflammatory genes are a key contributor to AS progression (Kim et al., 2020). Conversely, reduced acetylation in genes regulating lipid metabolism can impair lipid clearance, exacerbating plaque formation and instability.

Recent studies have demonstrated the significance of histone acetylation in regulating genes such as APOE, which plays a pivotal role in lipid metabolism and atherosclerosis. Aberrant acetylation of histones associated with the APOE gene promoter has been linked to decreased APOE expression, impairing lipid transport and clearance, thus contributing to atherosclerotic plaque accumulation (Saavedra et al., 2021). Additionally, animal studies have shown that therapeutic modulation of histone acetylation through HDAC inhibitors can reverse these adverse gene expression patterns, leading to reduced plaque burden and improved cardiovascular outcomes (Kruithof et al., 2018).

These findings suggest that correcting histone acetylation dysregulation holds potential as a therapeutic strategy for managing AS and CAD progression. Targeting histone acetylation with precision therapies could restore the normal expression of genes critical to lipid metabolism, inflammation, and plaque stability, offering a novel approach to improving patient outcomes in cardiovascular disease.

Targeting Histone Acetylation in the treatment of AS and CAD

Figure 3: Histone modifications and their therapeutic agents in AS/CAD

Figure 3 lists various histone acetylation modifications implicated in atherosclerosis and coronary artery disease alongside the corresponding drugs or therapeutic agents that target these modifications. The table categorizes histone modifications by type, identifies the affected histone residues, and lists the specific drugs used to inhibit or modulate acetylation activity.

Preclinical studies have demonstrated the efficacy of HDAC inhibitors in attenuating atherosclerosis progression and reducing plaque inflammation and vulnerability (Zaina et al., 2015). For example, treatment with HDAC inhibitors such as vorinostat and entinostat has been shown to reduce atherosclerotic lesion size and inflammation in animal models (Zheng et al., 2018). Vorinostat, a broad-spectrum HDAC inhibitor, and Entinostat, which targets class I HDACs, promote histone acetylation by inhibiting HDAC activity. This alteration leads to the relaxation of chromatin, which allows for increased transcriptional activity. As a result, it may influence genes related to vascular inflammation, endothelial dysfunction, and the stability of plaques within the arteries.

Regarding APOE, while direct studies linking HDAC inhibitors to APOE expression in AS are limited, the influence of histone acetylation on lipid metabolism and inflammation—processes influenced by APOE genotype—suggests potential indirect effects. These findings underscore the promising role of histone acetylation modulation as a therapeutic strategy in managing atherosclerosis. Consequently, this has spurred interest in developing HDAC inhibitors as potential therapeutics for atherosclerosis and CAD.

While direct evidence linking HDAC inhibitors to APOE expression in atherosclerosis remains limited, the observed effects of histone acetylation on lipid metabolism and inflammation—both processes affected by APOE genotype—suggest significant indirect relationships. These insights highlight the potential of modulating histone acetylation as a therapeutic strategy for managing atherosclerosis. This growing understanding has generated considerable interest in the development of HDAC inhibitors as promising candidates for treating atherosclerosis and coronary artery disease (CAD).

Advancing Precision Medicine in Cardiovascular Therapies

The treatment of atherosclerosis and coronary artery disease (AS/CAD) has made remarkable strides over recent decades thanks to advancements in medical science and our growing understanding of disease mechanisms. Emerging research into the genetic and epigenetic underpinnings of AS/CAD is providing new targets for therapeutic intervention. By delving into the genetics of these conditions, we can now better predict disease progression and individual responses to treatments. This section explores the potential of histone deacetylase (HDAC) inhibitors and other next-generation therapies in AS/CAD, addressing current challenges and future solutions. These drugs include histone deacetylase (HDAC) inhibitors such as vorinostat and panobinostat. Both have demonstrated efficacy in preclinical models by affecting a range of genetic targets and systemic pathways.

While histone acetylation presents a promising therapeutic target, there are several challenges in translating these findings into effective treatments. HDAC inhibitors target a wide range of genetic pathways, which can complicate their application by leading to off-target effects that may cause unintended consequences in other biological processes.

Researchers are exploring ways to overcome these obstacles by developing more specific targeting methods, such as focusing on particular genetic variants like the APOE4 allele. In addition, advances in drug delivery systems, such as nanoparticles and antibody-conjugated systems, show potential for enhancing selectivity. For instance, nanoparticles have been used to deliver drugs to the heart and vasculature, demonstrating their potential to target disease sites more effectively (Wei et al., 2017). Further studies are needed to refine these delivery methods and enhance the specificity of treatments.

One critical aspect is optimizing drug delivery methods to ensure efficient targeting and uptake in diseased tissues while minimizing off-target effects in healthy organs. Current research is focusing on innovative approaches, such as nanoparticles and antibody-conjugated delivery systems, which can selectively target HDAC inhibitors to specific tissues like the heart and vascular endothelium. This targeted delivery enhances therapeutic efficacy while reducing systemic toxicity (Wei et al., 2017).

To enhance the efficacy of HDAC inhibitors, it is essential to refine drug delivery systems. Innovations such as nanoparticle-based delivery and antibody-conjugated systems seek to enhance the targeting of affected tissues, like the heart or vascular endothelium, while minimizing systemic exposure, thereby improving the therapeutic efficacy of HDAC inhibitors. For example, antibody-conjugated systems can selectively deliver HDAC inhibitors to specific disease markers, improving therapeutic outcomes and reducing off-target effects. Research is ongoing to identify specific disease markers and develop targeted delivery strategies that could significantly improve the treatment of AS/CAD. Optimization of drug delivery methods, identification of patient populations most likely to benefit from treatment, and mitigation of potential side effects are ongoing areas of investigation.

Pharmacogenomics plays a critical role in tailoring treatments based on individual genetic profiles. Variations in genes influencing drug metabolism and response can affect the efficacy and safety of HDAC inhibitors. By understanding these genetic differences, clinicians can select and adjust treatments more precisely. For example, genetic variations affecting the metabolism of HDAC inhibitors can guide clinicians in adjusting dosages to maximize therapeutic benefits while minimizing adverse effects (Kang & Lee, 2018; Zhao et al., 2021). This personalized approach allows healthcare providers to tailor treatments based on a patient’s unique genetic profile, improving overall outcomes. Integrating whole genome sequencing and pharmacogenomic data can further enhance the precision of AS/CAD treatments. This personalized approach ensures that treatments are more precisely matched to the genetic characteristics of the patient, thereby improving overall outcomes in managing diseases like atherosclerosis. Additionally, understanding the genetic underpinnings of individual responses to HDAC inhibitors can lead to the development of targeted therapies that address specific genetic mutations, further advancing the field of precision medicine (Lee et al., 2020).

Conclusion

The research into atherosclerosis (AS) and coronary artery disease (CAD) has highlighted the critical role of histone modifications, particularly histone acetylation, in the regulation of key processes such as vascular inflammation, endothelial dysfunction, and plaque stability. The therapeutic potential of histone deacetylase (HDAC) inhibitors has emerged as a promising avenue, with studies showing their ability to modulate gene expression and reduce plaque burden. Advances in precision medicine, including personalized approaches based on genetic profiles, have further emphasized the importance of targeted treatments. Moreover, innovative drug delivery systems, such as nanoparticles and antibody-conjugated therapies, aim to enhance tissue-specific targeting, reducing systemic toxicity and improving efficacy. Despite this progress, challenges persist. However, continued research and the refinement of these approaches hold the potential to revolutionize AS/CAD treatment and improve patient outcomes.

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