Unlocking the Secrets of Atherosclerosis
Atherosclerosis is a chronic disease that occurs when the walls of the arteries become thickened and hardened, typically due to the accumulation of plaque. This plaque is made up of cholesterol, calcium, and other substances in the blood. As the plaque builds up, it can narrow or block the artery, making it harder for blood to flow through. This can increase the risk of a heart attack, stroke, or other serious problems.
During the process of Atherosclerosis, low-density lipoprotein (LDL) particles, known as „bad cholesterol“, enter the inner lining of the artery. These LDL particles are then oxidized, forming so called oxLDL particles. Macrophages (immune cells) then scavenge the oxLDL and convert it into foam cells. These cells accumulate and gradually form fatty streaks, leading to the migration and proliferation of medial vascular smooth muscle cells (VSMCs) and the emergence of unstable plaques. These plaques can rupture, causing thrombus formation and severe cardiovascular or cerebrovascular events such as myocardial infarction and stroke.
The effects of transcription factors on VSMCs
Now, a new review has been published summarizing the effects of different transcription factors on VSMCs during the atherosclerotic process. These transcription factors play a role in phenotypic transformation, foam cell formation, proliferation, migration, calcification, and apoptosis of VSMCs. Ideed, enhancement or inhibition of these factors could regulate the development of atherosclerotic lesions. This in turn could provide a new direction for understanding and treating atherosclerosis.
In healthy vessels, VSMCs have a contractile phenotype characterized by expression of specific marker genes such as ACTA2 and MYH11. However, in the context of atherosclerosis, these cells undergo a process called the phenotypic switch. This process is characterized by a loss of expression of these marker genes and an increase in proliferation and migration. They then discuss the roles of several specific transcription factors in regulating the phenotypic switch, including MYOCD, PTEN, and TCF21. The text also touches on the role of KLF4 and NF-κB, and how certain inhibitors can be used to prevent the phenotypic switch.
The role of OCT4, KL4, NRF2, GAX, NFAT5 and PAX9
It explains that certain transcription factors, such as OCT4, appear to promote an athero-protective phenotype and the loss of which weakens the plaque stability and accelerates the development of atherosclerotic lesions. However, KLF4, another transcription factor, appears to regulate OCT4 expression in VSMCs and loss of KLF4 may lead to the downregulation of OCT4. The authors then talk about other transcription factors like NRF2 and PAX9 which also contribute to the development of atherosclerosis, either in promoting or alleviating the condition. There are other transcription factors like KLF2 or KLF5 may also activate OCT4 and subsequently regulate the early stages of VSMC phenotypic transitions.
The role of TCF21, RUNX2, STAT, SLUG and NF-κB
It states that TCF21 is up-regulated during the formation of atherosclerotic lesions and promotes the transformation of vascular smooth muscle cells (VSMCs) into a fibroblast-like phenotype, called „fibromyocytes.“ This process weakens the plaque stability and accelerates the development of the disease, and whether these derived cells eventually promote or inhibit atherosclerotic lesions needs to be further verified. The text also mentions other transcription factors like RUNX2, STAT, SLUG, and NF-κB that also have role in the process of phenotypic transition in the VSMCs, and that the VSMCs can differentiate into foam cells, a lipid-rich phenotype, which are found in both advanced and early stages of the disease.
In addition to the above-mentioned, other transcription factors also up-regulate and promote VSMC proliferation and migration in atherosclerotic lesions. Overexpression of hypoxia-inducible transcription factor-1 (HIF-1), a ubiquitous transcription factor that regulates cellular oxygenation and metabolic adaptation to hypoxic states, up-regulates macrophage migration inhibitory factor (MIF) expression in VSMCs.
Proliferation and migration
Let us next look at the relationship between abnormal proliferation and migration of vascular smooth muscle cells and the development of atherosclerotic lesions. The authors state that factors such as growth factors, vasoactive substances, inflammatory mediators, matrix components and cell-cell interactions can stimulate VSMC proliferation and migration, leading to excessive fibrous tissue formation and intimal thickening, which contribute to restenosis after angioplasty. Furthermore, there are specific transcription factors such as KLF4, CHOP, KLF5, RUNX2, STAT, SLUG, and NF-κB that regulate the proliferation and migration of VSMCs. This leads to different phenotypes of VSMCs and influences the development of atherosclerosis.
Furthermore, the authors illustrate how abnormal apoptosis of VSMCs is closely associated with the development of atherosclerotic plaques. It also plays a critical role in restenosis after angioplasty of human coronary arteries. They then describe various factors that can cause VSMC apoptosis, such as CHOP, a protein that promotes ER stress-related apoptosis, and FOXO3, a transcription factor that activates cell death pathways. Moreover, they highlight that interactions of these factors are complex and can have both beneficial and detrimental effects on VSMC survival.
This text also discusses the process of calcification, which is characterized by calcium deposition in the vascular walls and reduces the elasticity and compliance of the vessel. Calcification can begin at the initial stages of atherosclerosis, accelerate during its development, and ultimately lead to plaque destabilization. The primary cause of vascular calcification is the osteogenic transition of differentiated VSMCs. Various transcription factors have been linked to the increased prevalence of vascular calcification, such as RUNX2, FOXO1/3, NF-κB and CHOP. Mechanisms of these factors to calcification is through AKT signaling, binding to the RUNX2 promoter, and activation of ER stress, amongst others.
So, what do we learn from these findings and how can we work on them?
- Transcription factors are important regulators of VSMCs during the development of atherosclerotic lesions.
- Recent advances in biotechnology have provided new insights into the complex networks of transcription factors and their target genes.
- Further research on the regulation of transcription factors in VSMCs may lead to the development of new therapeutics for the treatment of atherosclerosis.