Table of contentsSummaryIntroductionDiscussion1. Distinct cell fatesa. Apoptotic VSMCb. Senescent VSMC2. Several levels of regulationa. Transcriptional regulation: myocardinb. Post-transcriptional regulation: miRNA3. Lineage tracing: dependence on embryonic originConclusionReferencesAbstractCoronary heart disease (CAD) is by far the most common cardiovascular disease leading to death in the United States. According to a report filed by the Centers for Disease Control and Prevention (CDC), the disease causes up to 370,000 deaths per year. Over the years, researchers have been able to identify key underlying factors that could directly or indirectly lead to CAD, such as atherosclerosis (AS), miRNA regulation, and hypercholesterolemia. Additionally, different biomarkers were carefully examined and cell-specific lineages were traced to study the proliferation and differentiation of different cell types involved in AS. However, much controversy and debate has still occurred over the specific roles of VSMCs. The aim of this review is to rigorously evaluate current research perspectives on the involvement of VSMCs in AS progression, and how different factors interacting with VSMCs might have contributed to distinct pathological phenotypes. Say no to plagiarism. Get a tailor-made essay on “Why violent video games should not be banned”?Get the original essayIntroductionIn order to implement and refine current therapeutic methods for the treatment of coronary heart disease (CAD), it is essential to understand the underlying biochemical mechanisms. and the mechanical causes that lead to disease initiation and progression. Atherosclerosis (AS) is a common chronic disease that begins to progress in childhood. AS is usually initiated by hypertension or hypercholesterolemia, which damages the thin layer of endothelium of the artery, leading to aggregation of white blood cells, particularly macrophages and other macrophage-derived cells, to degrade the accumulation low density lipoprotein (LDL) and any potential pathogens. The chronic presence of WBC at the damaged site eventually led to the formation of fibrous plaque, composed of multiple lipoproteins and necrotic WBC debris, capped with VSMC and fibrous tissue. Once the plaque has reached a size comparable to the diameter of the arteries, patients face the danger of acute removal of fibrous plaque which consequently leads to the famous coronary artery disease (CAD) due to blood clotting (or thrombosis) and immediate. Death of cardiomyocytes. VSMCs are involved in various aspects of AS progression. VSMCs are the primary producer of extracellular matrix (ECM) in response to atherogenic signals such as INF. By secreting several types of adhesion molecules, including VCAM-1 and ICAM-1, VSMCs also serve as docking sites for monocytes and leukocytes to stabilize damaged cell layers against apoptosis and promote the atherogenesis using platelets. Previously, this process was known to be a mechanism for protecting damaged vessel walls. However, recent investigations have revealed a different story in which they have discovered that VSMC phenotypes and lineages play a major role in determining the trajectory of disease progression. A variety of lipoproteins and ligands could induce a dramatic change in both the morphology and functionality of VSMCs, changing them from inhibiting AS to promoting it. Despitethe efforts made to elucidate the underlying mechanism of atherosclerosis (AS) and coronary heart disease (CAD), the academic society is still trying to characterize the biochemical and mechanical properties of VSMCs from three major angles: 1) the fate of VSMCs, whether normal, senescent or apoptotic; 2) biochemical interactions through epigenetic regulation or ligand-receptor binding; 3) origin of VSMCs by lineage tracing to determine cell type specificity of biomarkers. Although not able to give a complete picture of the situation, this article will cover in detail the experimental setups, critical results, and potential caveats within these three topics.Discussion1. Distinct cell fatesa. Apoptotic VSMCsVascular smooth muscle cells (VSMCs) play an important role in the process of post-injury vascular regeneration due to their ability to produce a large number of structural proteins, including type I and III collagen, for the reconstruction of the Damaged MEC. It has long been observed in in vitro culture that the presence of VSMC within the culture of monocytes inhibits their apoptosis, which is correlated with the phenomenon of accumulation of macrophages at the injured site, causing chronic inflammation. However, pathological responses related to the presence of apoptotic VSMC were rarely mentioned in previous studies. Bennett et al. from the University of Cambridge noticed this gap and conducted a series of experiments to try to elucidate the determining biochemical factor behind the anti-apoptotic phenotype of VSMCs. Using transgenic mice with a VSMC-specific toxin receptor (hDTR) and deficient in atherosclerosis-prone apolipoprotein E, his group was able to elucidate that VSMC death is insufficient to induce inflammation or any type of remodeling. vessels. However, if apoptotic VSMCs appeared in established plaque, they would only acquire the capacity to induce atherosclerotic plaque vulnerability. Although rarely observed in vivo, Bennett et al. further demonstrated that this apoptotic phenotype of VSMCs is sufficiently potent to trigger adverse clinical outcomes in early stage AS. Again, hDTR transgenic mice were used as an animal model to study the consequences of VSMC apoptosis by administering diphtheria toxin (DT), which binds to hDTR and induces cell apoptosis, continuously for 10 at 15 weeks with a high-fat diet, imitating the pathological phenomena. hypercholesterolemia. It was widely accepted that VSMCs are essential to the vascularization process. Nevertheless, with minimal presence of apoptotic VSMCs in the early stage of AS, pathological features such as thinning of the fibrous cap and development of a necrotic core can already be observed in the arteries of treated mice, indicating that this apoptotic phenotype of VSMCs could be a useful biomarker in predicting disease progression at an early stage and assessing the possibility of plaque appearance at an advanced stage. While Bennett et al. attempt to argue that apoptotic VSMCs have a detrimental effect on patient well-being, a set of proteins called NF-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1, identified by a group of researchers from Showa. The University School of Pharmacy helps regulate the fate of VSMCs by detecting reactive oxygen species (ROS) that induce oxidative stresses due to vascular damage. Their results showed that Nrf2-induced VSMC apoptosis could positively contribute to the formation of the neointimal layer and otherVascular remodeling events after vascular injury. By downregulating the anti-apoptotic signaling molecule Keap1 and upregulating Nrf2 upon injury, in vivo models demonstrated significantly faster revascularization with VSMC apoptosis, preventing the system from undergoing hyperplasia . While recognizing the validity of their point of view, both investigators noted that neither the sex nor the age of the mice used was specified in the first experiments, and that only male mice were used in the second. Gender plays a critical role in cardiovascular events, and the coronary heart disease (CAD) risk profile is particularly associated with women's reproductive status and the transition to menopause. Additionally, unlike humans, female mice reach their age of sexual maturity in four to six weeks, so their hormone levels, as well as other physiological functions, could have skewed the experimental results to a large extent. measure. It would therefore be desirable to specify the sex and reproductive status of animal models used in any cardiovascular research.b. Senescent VSMCsRas have been identified as a potent stimulus in various cellular events involving vascularization and angiogenesis. Upon arterial injury, Ras can be activated to induce senescence of vascular smooth muscle cells during atherogenesis. Minamino et al. presented evidence not only of Ras activation, but also of downstream signals such as ERK signaling and immunostaining images for histological samples in vitro and in vivo, demonstrating colocalization of senescent VSMCs with inflammation chronic in atherosclerotic plaque established by antibodies against senescence associated -galactosidase (SA--gal) and -smooth muscle actin. (Minamino Tohru et al., 2003) This evidence suggests that there may be a heterogeneous population of VSMCs within the plaque established to help achieve the homeostatic state of the neointima layer formed by the proteins of the ECM, macrophages and macrophage-derived lipids, and various forms of vascular smooth muscle cells (VSMCs) that function cooperatively but distinctly. Nevertheless, the biomarkers used to identify precise subpopulations of this heterogeneous healing complex may not be specific enough to support the assertion that these antibody-stained populations were exclusively VSMCs. This particular caveat will be discussed in later sections where other investigators have questioned the validity of using these surface proteins as unique biomarkers for VSMCs through the embryo line trance method for study the proliferation and differentiation of VSMC.2 progenitors. Several levels of regulationa. Transcriptional Regulation: Myocardin Recent efforts to further characterize the phenotypic traits of VSMCs within the atherosclerotic plaque have revealed new evidence that chronic cholesterol loading of VSMCs dramatically alters them into a dysfunctional macrophage-like phenotype. The Fisher group observed in culture plates that VSMCs can undergo a phenotype change in the presence of cholesterol by staining for specific markers of vascular smooth muscle cells (ACTA2) and macrophages (CD68). Their biochemical results were supported by transcriptome profiling and qRT-PCR to quantitatively analyze the expression level of these proteins. Armed with this evidence, they then tested whether external stimulation causedthe downregulation of two genetic components crucial for VSMC contractility: the transcription factor myocardin and its co-activator serum response factor (SRF). Indeed, the Fisher group reported that the level of SRF was reduced by approximately 60% compared to that of the control group, and the level of myocardin was downregulated to only 25% compared to that of the control group, indicating a significant loss of contractility and mobility of VSMCs to migrate towards the injured site and participate in the revascularization of the damaged vascular wall. Although it lacks data from an in vivo study, which would have been more clinically relevant, this result further deeply complicates the controversy over the definitive functionality of VSMCs, as it is extremely difficult to directly monitor the physiological state of a patient in real time. Ackers-Johnson et al. also reported the inhibitory role of myocardin in VSMC activation, preventing the inflammatory response by downregulating the expression levels of several cytokines, chemokines, and adhesive molecules for macrophage anchoring. Attenuation of macrophage accumulation was also observed by Ackers-Johnson et al. in hypercholesterolemic ApoE -/- mouse models administered with myocardin-encoded adenoviruses compare to that of the control group. These findings provide insight into the physiological regulation of VSMCs at transcriptional levels, providing potential therapeutic targets for AS and CAD to mitigate adverse effects on your immune system and reduce the risk of AS plaque rupture with progression of coronary artery disease. . However, Yuliya et al. and Ackers-Johnson et al. presented several potential therapeutic targets to attenuate hyperplasia and proposed possible interactions between VSMCs and dysfunctional macrophages due to their phenotypic similarities.b. Post-transcriptional regulation: miRNAChoe et al. focused their research on the proliferation and differentiation of VSMCs regulated by microRNAs. MicroRNAs are single-stranded non-coding RNA molecules that can bind to the 3' untranslated region of mRNA to control the post-transcriptional activity of that particular mRNA. Of major interest, Choe et al. showed that miR-34c plays a crucial role in the process of neointimal hyperplasia in vitro and in vivo, alongside a protein called stem cell factor (SCF). By careful study, these researchers discovered that miRNA-34c targets SCF, which is thought to induce the proliferation and migration of VSMCs in the early stages of atherosclerosis. Histological staining samples of rat arterial tissue were analyzed microscopically to study the pathological effects of miRNA-34c overexpression in vivo, and significant downregulation of SCF is observed with severely attenuated atherogenesis and vascularization. A caveat when comparing these data with those of other researchers is that Choe et al. used male Sprague-Dawley rats while previous investigators largely used ApoE −/− hypercholesterolemic mouse models. Nevertheless, these results qualitatively illustrate that the proliferation, migration and differentiation powers of VSMCs are regulated by a combination of genetic and epigenetic factors, and that further research needs to be carried out taking into account all these different regulators to characterize with precision the pathogenesis and progression of coronary heart disease. arterial disease.3. Lineage tracing: dependence on embryonic originAn even deeper controversy concerns whether VSMCs are responsible fordeterioration of atherosclerosis due to plaque rupture for several reasons: 1) there is no definitive biomarker for VSMCs due to antigen loss or contact transfer during disease. progression; 2) VSMCs derived from different embryological origins tend to have distinct functions and marker expressions; 3) there are other tissues or cell types that express ACTA2 and MYH11 at different stages of differentiation. Cheung et al. presented a possible solution to this problem by artificially inducing different types of VSMCs from human pluripotent stem cells (hPSCs) using growth factors, hormones or chemicals. After the initial induction of differentiation, there are three intermediate lineages: neuroectoderm (NE), lateral plate mesoderm (LM), and paraxial mesoderm (PM). Cheung et al. showed that these origin-specific VSMC subtypes require different differential stimuli for fate commitment and distinct biological responses to cytokine stimulations. These results could open a new chapter in research on the characteristics of VSMCs and give rise to unexpected therapeutic targets due to the change in classification and the need to refine the method. Conclusion We conclude that there are major controversies over the exact functions and phenotypic traits of VSMCs during the progression of atherosclerosis and coronary heart disease. Although many efforts have been made to elucidate the characteristic similarities and potential interaction between VSMCs with neighboring endothelial cells and accumulated macrophages, many questions still remain unanswered due to the extreme complexity of biological systems. Evidence for both promotion and inhibition of AS has been provided by different investigators trying to argue the specific function of VSMCs at a specific stage of the disease. However, when it comes to understanding a life-threatening illness such as coronary heart disease, several factors must always be considered to oversee the systematic response. Keep in mind: this is just a sample .Get a personalized article now from our expert editors.Get a personalized essayFinally, we believe that it would be impossible to elucidate the full picture of VSMC-induced CAD without definitive analysis and rigorous characterizations of VSMC interactions with other micro/macromolecules. Therefore, further investigations need to be conducted before the selection of therapeutic targets in human patients.ReferencesAckers-Johnson, M., Talasila, A., Sage, AP, Long, X., Bot, I., Morrell, NW ,… Sinha , S. (2015). Myocardin regulates the activation and inflammatory diseases of vascular smooth muscle cells. Arteriosclerosis, thrombosis and vascular biology, 35(4), 817-828. https://doi.org/10.1161/ATVBAHA.114.305218 Ashino, T., Yamamoto, M., and Numazawa, S. (2016). The Nrf2/Keap1 system regulates vascular smooth muscle cell apoptosis for vascular homeostasis: role in neointimal formation after vascular injury. Scientific Reports, 6, 26291. https://doi.org/10.1038/srep26291 Beery, A. K. and Zucker, I. (2011). Gender bias in neuroscience and biomedical research. Neuroscience and Biobehavioral Reviews, 35(3), 565-572. https://doi.org/10.1016/j.neubiorev.2010.07.002CDC, NCHS. Underlying cause of death 1999-2013 from the CDC WONDER online database, published in 2015. Data comes from the Multiple Cause of Death Files, 1999-2013, compiled from data provided by all 57 jurisdictions in the civil status through the cooperative program of.114.304029