Atherosclerosis: Mechanisms, Pathways, and Therapeutic Approaches

Atherosclerosis represents one of the most significant health challenges of our time, serving as the primary underlying pathology for a range of cardiovascular diseases that remain the leading cause of mortality and morbidity worldwide. This comprehensive report explores the intricate mechanisms driving atherosclerotic disease, the cellular and molecular pathways involved, and evaluates both established and emerging therapeutic approaches. Atherosclerosis is fundamentally characterized by the progressive formation of lipid-rich plaques within arterial walls, resulting from complex interactions between lipid metabolism, inflammation, oxidative stress, and cell death processes. Understanding these mechanisms has advanced significantly in recent years, leading to more targeted therapeutic strategies that extend beyond traditional risk factor management.

Pathophysiology of Atherosclerosis

Fundamental Disease Process

Atherosclerosis is a chronic inflammatory condition that affects various arteries throughout the body, characterized by the formation of focal thickenings in the intimal layer of the arterial wall, known as atherosclerotic plaques18. The disease process involves multiple stages, beginning with endothelial dysfunction, followed by the formation of a new endothelial layer, lipid sediment accumulation, foam cell formation, plaque development, and eventually plaque rupture which can trigger thrombotic events12. The progression from early fatty streaks to advanced unstable plaques occurs over decades, typically remaining asymptomatic until significant arterial stenosis occurs or a plaque ruptures, causing downstream ischemic damage15.

The pathogenesis of atherosclerosis was once viewed primarily as a lipid storage disease, but contemporary understanding recognizes it as a complex immuno-metabolic disorder involving chronic inflammation, oxidative stress, epigenetic factors, and metabolic dysfunction19. This multifactorial nature explains why therapies targeting single mechanisms have often shown limited efficacy and highlights the need for comprehensive approaches addressing multiple pathways simultaneously15. Extensive epidemiological data have demonstrated that risk factors such as diabetes mellitus significantly accelerate atherogenesis, making these populations particularly vulnerable to cardiovascular complications10.

Inflammatory Mechanisms

Inflammation stands at the core of atherosclerotic disease, with multiple inflammatory pathways driving disease initiation and progression11. Recent evidence has validated the inflammatory hypothesis of atherosclerosis through clinical trials such as CANTOS and COLCOT, which demonstrated that targeting inflammatory mediators can reduce cardiovascular events independent of lipid-lowering effects11. A central component of the inflammatory response in atherosclerosis is the NLRP3 inflammasome, which acts as a signal transducer of the immune system and plays a critical role in the onset and progression of atherosclerotic disease5.

The NLRP3 inflammasome drives the production of pro-inflammatory cytokines such as IL-1β and IL-6, creating a cascade that promotes endothelial injury, foam cell formation, and pyroptosis5. Downstream of this pathway, the co-stimulatory dyad CD40L-CD40 and tumor necrosis factor-receptor associated factors (TRAFs) further amplify inflammatory responses11. This inflammatory milieu recruits monocytes to the arterial wall, where they differentiate into macrophages that ultimately transform into lipid-laden foam cells after ingesting modified lipoproteins17. Additionally, the chemokine system shapes immune cell recruitment and homeostasis through complex interactions that can be modulated to influence atherosclerotic progression11.

Oxidative Stress and Lipid Modifications

Oxidative stress represents a critical mechanism in atherogenesis, emerging when an imbalance exists between antioxidant capabilities and reactive species including oxygen, nitrogen, and halogen species8. This redox imbalance results in direct oxidation of cellular proteins, lipids, and DNA, activating cell death signaling pathways that accelerate plaque formation8. Notably, endothelial cells, which form the first barrier between blood and the arterial wall, are particularly susceptible to oxidative damage, leading to endothelial dysfunction that initiates the atherosclerotic process19.

Low-density lipoprotein (LDL) modification, particularly oxidation, represents a primary atherogenic transformation19. Oxidized LDL (oxLDL) undergoes a series of pathophysiological changes that enhance foam cell formation and plaque development19. The mechanisms of oxLDL's atherogenic effects include induction of endothelial dysfunction, formation of foam cells through uptake by macrophages via scavenger receptors, promotion of monocyte chemotaxis, stimulation of smooth muscle cell proliferation and migration, and activation of platelets19. These processes collectively contribute to plaque instability and, ultimately, rupture, which can trigger thrombotic events leading to myocardial infarction or stroke19.

Cell Death Mechanisms and Foam Cell Formation

Multiple cell death pathways contribute to atherosclerotic progression, with different forms of programmed cell death including apoptosis, autophagy, necroptosis, and pyroptosis involved in plaque development17. Recently, ferroptosis, a novel iron-dependent form of cell death, has been identified as a participant in atherosclerotic progression through increased endothelial reactive oxygen species (ROS) levels and lipid peroxidation4. Accumulated intracellular iron activates various signaling pathways for atherosclerosis, such as abnormal lipid metabolism, oxidative stress, and inflammation, which ultimately lead to disordered function of macrophages, vascular smooth muscle cells, and vascular endothelial cells4.

Foam cells, which are lipid-laden macrophages, play a pivotal role in the initiation and development of atherosclerosis17. Novel technologies including lineage tracing and single-cell RNA sequencing have revolutionized understanding of foam cell heterogeneity, identifying three main clusters of monocyte-derived foam cells in atherosclerotic plaques: resident-like, inflammatory, and those expressing triggering receptor expressed on myeloid cells-2 (Trem2hi)17. The formation of foam cells is regulated by cholesterol uptake, efflux, and esterification processes, with nuclear receptors, non-coding RNAs, and gut microbiota emerging as novel regulatory mechanisms17.

Mitochondrial Dysfunction

Mitochondria of blood and arterial wall cells have emerged as important factors in atherosclerosis initiation and development18. Significant experimental evidence connects oxidative stress associated with mitochondrial dysfunction to vascular disease18. Moreover, mitochondrial DNA (mtDNA) deletions and mutations are being considered as potential disease markers18. Dysfunctional mitochondria contribute to atherosclerosis through several mechanisms, including increased production of reactive oxygen species, impaired cellular metabolism, and activation of inflammatory pathways18. The recognition of mitochondria as disease-modifying factors opens new perspectives for atherosclerosis treatment through targeting mitochondrial function18.

Therapeutic Targets and Approaches

Established Pharmacological Interventions

Statin therapy remains the cornerstone of pharmacological management for atherosclerosis, with robust evidence supporting its efficacy in reducing cardiovascular events16. The Intensive Statin Treatment in Acute Ischaemic Stroke Patients with Intracranial Atherosclerosis - High-Resolution Magnetic Resonance Imaging (STAMINA-MRI) Trial demonstrated that high-dose statin treatment in statin-naive patients with symptomatic intracranial atherosclerosis significantly decreased plaque volume, wall area index, and stenosis degree16. The mechanism extends beyond lipid-lowering effects to include plaque stabilization, reduction of inflammation, and improvement of endothelial function16.

In addition to statins, anti-inflammatory approaches have gained traction following the validation of the inflammatory paradigm in clinical trials such as CANTOS and COLCOT11. These approaches target various aspects of the inflammatory cascade, including the NLRP3 inflammasome-driven IL-1β-IL6 axis11. Small molecule inhibitors targeting the TRAF6-CD40 interaction in macrophages have shown promise in reducing established atherosclerosis and plaque instability without causing immune side effects11. These targeted approaches represent a significant advancement from traditional anti-inflammatory strategies, which often carry substantial immunosuppressive side effects11.

Lifestyle Modifications and Risk Factor Management

Managing traditional risk factors for atherosclerosis, including hypertension, diabetes mellitus, smoking, and obesity, remains a proven approach to reducing disease burden1020. Particularly noteworthy is the impact of obesity management, as research has shown that both obesity severity and duration are associated with incident metabolic syndrome, which significantly increases atherosclerosis risk20. The Multi-Ethnic Study of Atherosclerosis demonstrated that higher obesity severity and longer duration were both associated with a higher odds of incident metabolic syndrome, challenging the concept of "metabolically healthy obesity"20.

Medical and surgical interventions for obesity have demonstrated benefits for atherosclerosis beyond their effects on typical risk factors, suggesting multiple mechanistic pathways through which weight management influences cardiovascular health3. This highlights the importance of comprehensive risk factor management as a proven approach to atherosclerosis prevention and treatment10. The benefits of these interventions are well-established through multiple large-scale clinical trials and epidemiological studies, making them cornerstone strategies in cardiovascular disease prevention10.

Emerging Therapies: Natural Products and Nutraceuticals

Natural products and nutraceuticals have gained significant attention as potential anti-atherosclerotic agents due to their generally favorable safety profiles9. Chinese herbal medicine has been used for the treatment of cardiovascular diseases for hundreds of years, though the mechanisms of action in preventing and treating atherosclerosis have not been well studied9. Increasing research is now revealing the cellular and molecular mechanisms behind these traditional remedies, building a bridge between traditional Chinese medicine and modern cardiovascular medicine9.

Berberine, an alkaloid compound derived from various plants, has emerged as one of the most promising natural products for atherosclerosis treatment12. Network pharmacology studies have identified multiple targets through which berberine may exert anti-atherosclerotic effects, including regulation of G1/S transition of mitotic cell cycle12. However, the panoramic mechanism of berberine against atherosclerosis requires further clarification to optimize its therapeutic application12.

Curcumin, a polyphenolic compound with numerous pharmacological activities, has shown protective effects against atherosclerosis through inhibiting the atherogenic properties of monocytes14. This includes reduction of inflammatory cytokine production, inhibition of monocyte adhesion and transendothelial migration, and prevention of intracellular cholesterol accumulation14. Despite these promising findings, the clinical efficacy of curcumin is limited by its poor bioavailability, highlighting the need for improved delivery methods14.

The edible genus Pleurotus, commonly known as oyster mushrooms, has demonstrated valuable medicinal attributes for the prevention and treatment of atherosclerosis7. At least ten different types of Pleurotus species have been reported to have anti-atherogenic capabilities, with six possessing high levels of anti-atherogenic compounds such as ACE inhibitor peptide, ergothioneine, chrysin, and lovastatin7. These mushrooms show potential for use as functional foods or as extracts from fruiting bodies or mycelium in alternative therapy for atherosclerosis, particularly through prevention and treatment of oxidative stress, hypertension, and hypercholesterolemia7.

Novel Therapeutic Approaches Under Investigation

Nanotechnology has emerged as a promising approach to enhance the delivery and efficacy of anti-atherosclerotic compounds6. Drug delivery systems have revolutionized therapeutic approaches, and researchers are exploring the potential of nano-mediated delivery of nutraceuticals as a strategy to target atherosclerotic sites6. This approach aims to boost the therapeutic efficiency of natural compounds while minimizing side effects, though more experimental evidence is needed to validate its clinical efficacy6.

Targeting ferroptosis represents another innovative strategy for atherosclerosis treatment4. Ferroptosis inhibition could potentially reduce endothelial damage, mitigate lipid peroxidation, and attenuate inflammatory responses in the arterial wall4. However, the molecular pathways through which ferroptosis affects atherosclerosis development and progression are not entirely understood, necessitating further research to develop effective therapeutic interventions4.

The modulation of the chemokine system through structure-function analysis has enabled the design of cyclic, helical, or linked peptides specifically targeting or mimicking interactions to limit atherosclerosis or thrombosis11. These approaches work by blunting myeloid recruitment, boosting regulatory T cells, inhibiting platelet activity, or specifically blocking atypical chemokines without notable side effects11. Such targeted interventions represent a significant advancement over broad-spectrum anti-inflammatory approaches, potentially offering superior efficacy with reduced adverse effects11.

Conclusion

Atherosclerosis represents a complex interplay of inflammatory, metabolic, and cellular processes that collectively drive the formation and progression of arterial plaques. The understanding of atherosclerosis has evolved significantly from viewing it as merely a lipid storage disease to recognizing it as a multifaceted immuno-metabolic disorder. This enhanced understanding has facilitated the development of targeted therapeutic approaches beyond traditional lipid-lowering strategies.

Established interventions, including statin therapy and comprehensive risk factor management, remain the foundation of atherosclerosis treatment with robust evidence supporting their efficacy. However, significant residual cardiovascular risk persists despite optimal conventional therapy, highlighting the need for novel approaches targeting specific pathways in atherosclerotic disease. Emerging therapies leveraging natural products, nanotechnology, and targeted modulation of specific inflammatory pathways hold promise for enhancing the management of atherosclerosis.

The future of atherosclerosis treatment likely lies in personalized approaches that combine established interventions with novel targeted therapies based on individual patient characteristics and disease mechanisms. Further research is needed to fully elucidate the complex pathways involved in atherosclerosis and to translate emerging therapeutic concepts into clinical practice. As our understanding continues to evolve, so too will our ability to effectively prevent and treat this pervasive and devastating disease.