Vascular Smooth Muscle Proliferation Research Articles

Atherosclerosis associated with Chlamydia pneumoniae: Dissecting the etiology

Chlamydia pneumoniae related infections and atherosclerosis are both common entities. Today, the literature presents an enormous amount of data regarding the role of C. pneumoniae in the development and sustainment of atherosclerosis and allowing us to comprehend the molecular mechanisms behind better. The implications of C. pneumoniae in atherogenesis include altered platelet function, hypercoagulability, macrophage dysfunction, vascular smooth muscle proliferation, and increased neutrophilic migration. Therefore, it would not be wrong to implicate that, C. pneumoniae plays important roles in almost every stage of atherogenesis. Furthermore, various serological markers suggestive of active or past C. pneumoniae infection are known to be associated with multiple clinical presentations, such as abdominal aortic aneurysms, subclinical atherosclerosis in the young individuals, aggravated atherosclerosis in heterozygous familial hypercholesterolemia. This review, as a result, aims to provide detailed insights into the pathophysiological mechanisms of atherogenesis associated with C. pneumoniae and its clinical implications.

Identification of oxidative phosphorylation-related genes in moyamoya disease by combining bulk RNA-sequencing analysis and machine learning.

Introduction: Moyamoya disease (MMD) is a chronic cerebrovascular disease that can lead to ischemia and hemorrhagic stroke. The relationship between oxidative phosphorylation (OXPHOS) and MMD pathogenesis remains unknown. Methods: The gene expression data of 60 participants were acquired from three Gene Expression Omnibus (GEO) datasets, including 36 and 24 in the MMD and control groups. Differentially expressed genes (DEGs) between MMD patients MMD and control groups were identified. Machine learning was used to select the key OXPHOS-related genes associated with MMD from the intersection of DEGs and OXPHOS-related gene sets. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), gene set enrichment analysis (GSEA), Immune infiltration and microenvironments analysis were used to analyze the function of key genes. Machine learning selected four key OXPHOS-related genes associated with MMD: CSK, NARS2, PTPN6 and SMAD2 (PTPN6 was upregulated and the other three were downregulated). Results: Functional enrichment analysis showed that these genes were mainly enriched in the Notch signaling pathway, GAP junction, and RNA degradation, which are related to several biological processes, including angiogenesis, proliferation of vascular smooth muscle and endothelial cells, and cytoskeleton regulation. Immune analysis revealed immune infiltration and microenvironment in these MMD samples and their relationships with four key OXPHOS-related genes. APC co-inhibition (p = 0.032), HLA (p = 0.001), MHC I (p = 0.013), T cellco- inhibition (p = 0.032) and Type I IFN responses (p < 0.001) were significantly higher in the MMD groups than those in the control groups. The CSK positively correlated with APC co-inhibition and T cell-co-inhibition. The NARS2 negatively correlated with Type I IFN response. The SMAD2 negatively correlated with APC co-inhibition and Type I IFN response. The PTPN6 positively correlated with HLA, MHC I and Type I IFN responses. Discussion: This study provides a comprehensive understanding of the role of OXPHOS in MMD and will contribute to the development of new treatment methods and exploration of MMD pathogenesis.

NKX2-5 regulates vessel remodeling in scleroderma-associated pulmonary arterial hypertension.

NKX2-5 is a member of the homeobox-containing transcription factors critical in regulating tissue differentiation in development. Here, we report a role for NKX2-5 in vascular smooth muscle cell phenotypic modulation in vitro and in vascular remodeling in vivo. NKX2-5 is upregulated in scleroderma patients with pulmonary arterial hypertension. Suppression of NKX2-5 expression in smooth muscle cells halted vascular smooth muscle proliferation and migration, enhanced contractility, and blocked the expression of extracellular matrix genes. Conversely, overexpression of NKX2-5 suppressed the expression of contractile genes (ACTA2, TAGLN, CNN1) and enhanced the expression of matrix genes (COL1) in vascular smooth muscle cells. In vivo, conditional deletion of NKX2-5 attenuated blood vessel remodeling and halted the progression to hypertension in a mouse chronic hypoxia model. This study revealed that signals related to injury such as serum and low confluence, which induce NKX2-5 expression in cultured cells, is potentiated by TGF-β and further enhanced by hypoxia. The effect of TGF-β was sensitive to ERK5 and PI3K inhibition. Our data suggest a pivotal role for NKX2-5 in the phenotypic modulation of smooth muscle cells during pathological vascular remodeling and provide proof of concept for therapeutic targeting of NKX2-5 in vasculopathies.

The pharmaco-epigenetics of hypertension: a focus on microRNA.

Hypertension is a major harbinger of cardiovascular morbidity and mortality. It predisposes to higher rates of myocardial infarction, chronic kidney failure, stroke, and heart failure than most other risk factors. By 2025, the prevalence of hypertension is projected to reach 1.5 billion people. The pathophysiology of this disease is multifaceted, as it involves nitric oxide and endothelin dysregulation, reactive oxygen species, vascular smooth muscle proliferation, and vessel wall calcification, among others. With the advent of new biomolecular techniques, various studies have elucidated a gaping hole in the etiology and mechanisms of hypertension. Indeed, epigenetics, DNA methylation, histone modification, and microRNA-mediated translational silencing appear to play crucial roles in altering the molecular phenotype into a hypertensive profile. Here, we critically review the experimentally determined associations between microRNA (miRNA) molecules and hypertension pharmacotherapy. Particular attention is given to the epigenetic mechanisms underlying the physiological responses to antihypertensive drugs like candesartan, and other relevant drugs like clopidogrel, aspirin, and statins among others. Furthermore, how miRNA affects the pharmaco-epigenetics of hypertension is especially highlighted.

Statins-Beyond Their Use in Hypercholesterolemia: Focus on the Pediatric Population.

Statins are a class of medications primarily used in adults to lower cholesterol levels and reduce the risk of cardiovascular events. However, the use of statins in children is generally limited and carefully considered despite the well-documented anti-inflammatory, anti-angiogenic, and pro-apoptotic effects, as well as their effect on cell signaling pathways. These multifaceted effects, known as pleiotropic effects, encompass enhancements in endothelial function, a significant reduction in oxidative stress, the stabilization of atherosclerotic plaques, immunomodulation, the inhibition of vascular smooth muscle proliferation, an influence on bone metabolism, anti-inflammatory properties, antithrombotic effects, and a diminished risk of dementia. In children, recent research revealed promising perspectives on the use of statins in various conditions including neurological, cardiovascular, and oncologic diseases, as well as special situations, such as transplanted children. The long-term safety and efficacy of statins in children are still subjects of ongoing research, and healthcare providers carefully assess the individual risk factors and benefits before prescribing these medications to pediatric patients. The use of statins in children is generally less common than in adults, and it requires close monitoring and supervision by healthcare professionals. Further research is needed to fully assess the pleiotropic effects of statins in the pediatric population.

The relationship between hyperuricemia and hypertension: a short review of current evidence

The investigation of the relationship between hyperuricemia and hypertension is a captivating field in hypertension research. The final product of purine metabolism is uric acid (UA), and the elevation of serum UA (SUA) levels directly contributes to the development of hypertension. Numerous studies have substantiated that hyperuricemia is a significant risk factor for hypertension. Furthermore, initial clinical trials have demonstrated that therapeutic interventions aimed at reducing SUA levels lower blood pressure (BP) in individuals with hypertension attributed to hyperuricemia. Recent research has demonstrated that hyperuricemia can facilitate the onset of hypertension via multiple mechanisms, including oxidative stress, inflammation, diminished nitric oxide (NO) synthesis, activation of reactive oxygen species (ROS), insulin resistance, vascular smooth muscle proliferation, and renal impairment. Given the interconnectedness between hyperuricemia and hypertension, it is advantageous to identify potential therapeutic approaches for timely intervention in order to impede the advancement of hypertension in individuals with hyperuricemia. This article reviews the research progress on the pathogenesis of hyperuricemia-induced hypertension.

Reduced trans-myocardial extraction of endothelin-1 in cardiac allograft vasculopathy

Abstract Introduction Cardiac allograft vasculopathy (CAV) is a major cause of graft failure due to microvascular dysfunction and ischaemia following heart transplant. Endothelin-1 (ET-1) is an endothelium derived vasoconstrictor peptide with multiple adverse effects including vascular smooth muscle proliferation and pro-inflammatory signalling. Elevated circulating ET-1 has been associated with accelerated CAV. We assessed the trans-myocardial gradient (TMG: coronary sinus minus coronary artery concentration: negative=extraction, positive=secretion) of ET-1 in heart transplant patients to determine correlations with angiographic, Intravascular Ultrasound (IVUS) and Optical Coherence Tomography (OCT) features of CAV. Methods 23 patients underwent invasive coronary angiography, 3-vessel grey scale IVUS (Opticross, 60mHz, Boston Scientific) and OCT (Dragonfly, Abbott Vascular) to define morphological features of vasculopathy 18±3 months post-transplant. Paired blood samples were obtained from the guide catheter and coronary sinus at the time of coronary imaging. Plasma was analysed using specific enzyme-linked immunosorbent assay for ET-1 peptide quantification. Survival was determined 98±5 months after initial assessment. Results ET-1 TMG distribution was mostly in the negative range reflecting net extraction across the coronary vascular bed (median [IQR]: -0.23 [-0.54, -0.02] pg/ml). However, vessels with more severe CAV demonstrated significantly more positive TMG i.e. less ET-1 trans-myocardial extraction (IVUS Stanford Grade IV: -0.05 [-0.21, 0.13] pg/ml versus Stanford Grade I-III: -0.31 [-0.64, -0.11] pg/ml, p = 0.01). ET-1 TMG was positively correlated with mean intimal thickness on both IVUS and OCT (IVUS: Kendall’s tau-b = 0.254, p=0.02 and OCT: Kendall’s tau-b = 0.344, p&amp;lt;0.0001). Patients who died had net ET-1 secretion compared with surviving patients (died: 0.21 [0.19 - 0.24] versus surviving: -0.28 [-0.52, -0.17], p = 0.01). Conclusions In heart transplant patients, coronary arteries with more intimal thickening had less trans-myocardial extraction, and more secretion of ET-1. ET-1 secretion in CAV may mediate the distal microvascular dysfunction commonly seen in this condition. These findings suggest a rationale for testing ET-1 receptor antagonists as a treatment for CAV.ET-1 TMG and IVUS Stanford Grade of CAVET-1 TMG and OCT derived MIT

Abstract 17654: Sarpogrelate versus Clopidogrel for Arterial Interventions Systematic Review and Meta Analysis

Background: Sarpogrelate has been used to alleviate ischemic changes by preventing thrombosis, vasoconstriction, and vascular smoothmuscle proliferation. The worldwide use of Sarpogrelate is arguable due to the lack of reliable data regarding its efficacy and safety.Accordingly, our meta-analysis aims to compare the complications after receiving Sarpogrelate with Aspirin (S&amp;A) vs. Clopidogrel withAspirin (C&amp;A) as part of dual anti-platelet therapy in patients with endovascular intervention. Methods: Multiple electronic databases weresearched to identify relevant articles, including MEDLINE, Cochrane CENTRAL, Scopus, Google Scholar, Web of Science, and EMBASE. Allclinical studies that investigated the complication after performing Sarpogrelate versus clopidogrel with Aspirin for arterial interventionswere included in the meta-analysis. Reviews, case reports, conference abstracts, editorials, and animal studies were all excluded. Data wereanalyzed by using comprehensive meta-analysis studies. A complete quality assessment was performed using the Cochrane Risk of Bias toolversion 2 for randomized clinical trials (RCTs). Results: A total of 2588 studies were screened, with three studies included. Two multicenterRCTs and one retrospective cohort study including 527 patients (251 S&amp;A and 276 C&amp;A) were included. The overall quality was high in 2studies and fair in one. No statistically significant difference in restenosis, mortality, and bleeding risk as follows, respectively: (RR:0.81, 95%CI:0.52-1.2, P-value:0.36), (RR:0.37, 95% CI:0.06-2, P-value:0.25) and (RR:0.4, 95% CI:0.13-1.19, P-value:0.1). Conclusion: The antithromboticeffects of Aspirin with Sarpogrelate after vascular intervention are comparable to those of Aspirin plus Clopidogrel. Further large clinicalstudies are required to identify the actual difference in early and late complications after using Sarpogrelate versus clopidogrel.

Narrative Review: Peripheral Arterial Disease in Patients with Hyperuricemia and Gout.

To discuss what is currently known about the association and potential mechanistic interactions of hyperuricemia and gout with peripheral arterial disease (PAD). Gout patients are at increased risk for coronary artery disease, but less is known about their risk for PAD. Studies suggest that the presence of gout and hyperuricemia are associated with PAD independent of known established risk factors. Moreover, higher SU was found to be associated with greater odds of having PAD and was independently associated with decreased absolute claudication distance. Urate's role in free radical formation, platelet aggregation, vascular smooth muscle proliferation, and impaired endothelial vasodilation may promote atherosclerotic progression. Studies suggest that patients with hyperuricemia or gout are at higher risk for developing PAD. Evidence is stronger for the relationship between elevated SU and PAD than for gout and PAD, but more data is needed. Whether elevated SU serves as a marker or cause of PAD remains to be investigated.

The Clinical Significance of Salusins in Systemic Sclerosis—A Cross-Sectional Study

Background: Systemic sclerosis (SSc) is a connective tissue disease manifesting with progressive fibrosis of the skin and internal organs. Its pathogenesis is strictly associated with vascular disfunction and damage. Salusin-α and salusin-β, endogenous peptides regulating secretion of pro-inflammatory cytokines and vascular smooth muscle proliferation, may potentially play a role in SSc pathogenesis. Objectives: The aim of this study was to assess the concentration of salusins in sera of patients with SSc and healthy controls and to evaluate correlations between the salusins levels and selected clinical parameters within the study group. Materials and methods: 48 patients with SSc (44 women; mean age, 56.4, standard deviation, 11.4) and 25 adult healthy volunteers (25 women; mean age, 55.2, standard deviation, 11.2) were enrolled. All patients with SSc were treated with vasodilators and twenty-seven of them (56%) also received immunosuppressive therapy. Results: Circulating salusin-α was significantly elevated in patients with SSc in comparison to healthy controls (U = 350.5, p = 0.004). Patients with SSc receiving immunosuppression had higher serum salusin-α concentrations compared with those without immunosuppressive therapy (U = 176.0, p = 0.026). No correlation was observed between salusins concentrations and skin or internal organ involvement parameters. Conclusions: Salusin-α, a bioactive peptide mitigating the endothelial disfunction, was elevated in patients with systemic sclerosis receiving vasodilators and immunosuppressants. Increased salusin-α concertation may be associated with the initiation of atheroprotective processes in patients with SSc managed pharmacologically, which requires verification in future studies.

Von Willebrand factor: from figurant to main character in the scene of inflammation

von Willebrand factor: from figurant to main character in the scene of inflammation

MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription

Reactive oxygen species (ROS) promotes vascular injury and neointima formation in part by stimulating proliferation of vascular smooth muscle cells (VSMC). The underlying transcriptional mechanism, however, is not completely understood. Here we report that VSMC-specific deletion of MKL1 in mice suppressed neointima formation in a classic model of vascular injury. Likewise, pharmaceutical inhibition of MKL1 activity by CCG-1423 similarly mollified neointima formation in mice. Over-expression of a constitutively active MKL1 in vascular smooth muscle cells enhanced proliferation in a ROS-dependent manner. On the contrary, MKL1 depletion or inhibition attenuated VSMC proliferation. PCR array based screening identified forkhead box protein M1 (FOXM1) as a direct target for MKL1. MKL1 interacted with E2F1 to activate FOXM1 expression. Concordantly, FOXM1 depletion ameliorated MKL1-dependent VSMC proliferation. Of interest, ROS-induced MKL1 phosphorylation through MK2 was essential for its interaction with E2F1 and consequently FOXM1 trans-activation. Importantly, a positive correlation between FOXM1 expression and VSMC proliferation was identified in arterial specimens from patients with restenosis. Taken together, our data suggest that a redox-sensitive phosphorylation-switch of MKL1 activates FOXM1 transcription and mediates ROS fueled vascular smooth muscle proliferation. Targeting the MK-2/MKL1/FOXM1 axis may be considered as a reasonable approach for treatment of restenosis.

The effective constituent puerarin, from Pueraria lobata, inhibits the proliferation and inflammation of vascular smooth muscle in atherosclerosis through the miR-29b-3p/IGF1 pathway

Context Atherosclerosis (AS) is the main cause of cardiovascular and cerebrovascular diseases. Pueraria lobata (Willd.) Ohwi (Fabaceae) has a positive effect on improving these diseases. Objective The P. lobata effect on the proliferation and inflammation of vascular smooth muscle in AS and the potential mechanism were investigated. Materials and methods By feeding a high-fat diet to 8-week-old apolipoprotein E knockout mice, an atherosclerosis model was created. H&E and IHC staining were used to analyse the histopathology of mice. CCK-8, TUNEL, and scratch tests were used to detect cell proliferation, apoptosis, and migration after 24 h treatment, respectively. ELISA was performed to evaluate the level of IL-6 and IL-8. The target miRNA and its downstream target gene were screened by the bioinformatics method; RT-qPCR has conducted to analyse the expression of these genes. Results In the aortic tissue and serum of AS mice, puerarin can lower the expression of α-SMA and the inflammatory proteins IL-6 and IL-8. Puerarin (200 M) decreased hVSMC proliferation, migration, and IL-6 and IL-8 secretion by more than half. The inhibitory impact of puerarin on hVSMC was decreased by overexpression of miR-29b-3p. IGF1 was miR-29b-3p's downstream target gene. IGF1 expression increased almost 3-fold in AS mice and hVSMC, but miR-29b-3p mimic inhibited it. The effect of miR-29b-3p on hVSMC was reversed when IGF1 was overexpressed. Discussion and conclusions Puerarin inhibits the proliferation and inflammation of vascular smooth muscle in AS through the miR-29b-3p/IGF1 pathway. Puerarin may have a beneficial effect in the treatment of atherosclerosis and offer a novel therapy option.

Subclinical Hypertension-Mediated Organ Damage (HMOD) in Hypertension: Atherosclerotic Cardiovascular Disease (ASCVD) and Calcium Score.

Calcium controls numerous events within the vessel wall. Permeability of the endothelium is calcium dependent, as are platelet activation and adhesion, vascular smooth muscle proliferation and migration, and synthesis of fibrous connective tissue. Double-helix computerized tomography is a noninvasive technique that can detect, measure, and compare coronary calcification in the coronary arteries. Despite some convincing evidence about the prognostic value and usefulness of coronary artery calcium score (CACS) in the stratification of cardiovascular risk in the high risk general population and also in hypertensive patients, current guidelines for the management of hypertension, do not include such evaluation among the recommended procedures to be performed in the majority of patients even with the intent to detect hypertension-mediated organ damage (HMOD) in an early phase. On the contrary, the European Society of Cardiology guidelines for the diagnosis and management of chronic coronary syndromes, the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease, and the 2018 Cholesterol Clinical Practice Guidelines indicate that the evaluation of CACS may be of some usefulness in specific subpopulations, although this view is not accepted in the US Preventive Services Task Force document. Very recently, the European Society of Cardiology Guidelines on cardiovascular disease prevention in clinical practice stated that CACS estimation may be considered to improve risk classification around treatment decision thresholds. In conclusion, the use of CACS as a diagnostic tool is still controversial. While some evidence exists about is ability to improve stratification of cardiovascular risk in primary prevention, in particular in selected patients who are at intermediate or borderline risk of atherosclerotic cardiovascular disease, there is insufficient evidence to use it as a standard means to assess HMOD.

Construction of functional magnetic scaffold with temperature control switch for long-distance vascular injury

Fusion of endothelial monolayer for rapid reendothelialization is the key to vascular transplantation, which is crucial for remodeling long-distance (≥10 mm) vascular injury (LDVJ) and reducing the long-term repair period. Although silk fibroin (SF) has been widely prepared as a scaffold to repair vascular injuries, it is still challenging to remodel LDVJs. The design and manufacture of functional scaffolds with a rapid reendothelialization enhancement effect are helpful to solve this problem. Here, we developed a well-designed functional magnetic scaffold (MDP) with a temperature-controlled switch, intelligently regulating the release of magnetic nanoparticles (MNPs) to induce macrophages migration and M2 polarization. The results show that the radial support force of MDP is appropriately five times higher than that of pure silk fibroin scaffold (SFC), and the degradation of MDP is delayed, which is beneficial to maintaining the integrity of the scaffold. MDP induces the migration of macrophages, upregulates the expression of repair cytokines such as TGF-β, IL-10 and VEGF, and promotes the proliferation of mouse aortic vascular smooth muscle (MOVAS) cells. More importantly, the enhanced migration of macrophages at the phase transition temperature is more conducive to the proliferation and accumulation of vascular repair-related cells, which is conducive to rapid reendothelialization. In addition, MDP also significantly regulates the polarization of macrophages to M2 type, which is conducive to the secretion of repair cytokines to further promote vascular recovery. The evaluation of endothelial cells' adhesion and function also proved that MDP could increase the expression of vascular endothelial cadherin (VE-Cad) and collagen IV (COL IV) and has the potential for rapid reendothelialization. The replacement model in vivo animal experiments further proved that MDP exhibited a better repair effect than SFC, providing a new option for the repair of LDVJ in the future.

Roles and mechanisms of garlic and its extracts on atherosclerosis: A review.

The prevention and treatment of cardiovascular diseases (CVDs) have achieved initial results, but the number of CVDs patients will increase rapidly in the next 10 years. Atherosclerosis (AS) is a significant risk factor for CVDs. The impact of lifestyle and daily diet varies considerably between different countries and continents and has been shown to affect the development of various diseases such as diabetes and CVDs. Primary and secondary prevention using alternative supplements and methods to avoid or reduce the use of traditional pharmacological drugs have also become popular. One of the reasons for this is that pharmacological drugs with lipid-lowering, and blood pressure-lowering effects cause many side effects that may negatively impact the quality of life. Patients are now emphasizing reliance on lifestyle changes to reduce cardiovascular risks. Garlic is a medicinal and edible plant that has been used for a long time. In order to reveal garlic application in the prevention and treatment of AS, reviewing the latest domestic and international studies through searching databases. The result shows that the antiatherogenic role of garlic is eximious. And the mechanisms are mainly related to hypolipidemic, antioxidant, antithrombotic, inhibiting angiogenesis, protecting endothelial cells, anti-inflammatory, anti-apoptotic, inhibiting vascular smooth muscle proliferation, and regulating gut microbiota. The main signaling pathways involve AMPK/TLRs, Keap1/Nrf2, PI3K/AKT, PPARγ/LXRα, GEF-H1/RhoA/Rac, etc. The antiatherogenic actions and molecular mechanism of garlic were reviewed in this study to obtain a robust evidence basis for the clinical application and mechanistic study and provide a theoretical basis for further utilization of garlic.

Comprehensive insights into the function and molecular and pharmacological regulation of neuron-derived orphan receptor 1, an orphan receptor.

Neuron-derived orphan receptor 1 (NOR1), also called nuclear receptor subfamily 4 group A member 3 (NR4A3), is a nuclear receptor belonging to the NR4A family. Since no endogenous ligand has been identified to date, NOR1 is also referred to as an orphan receptor. NOR1 is expressed in a variety of cells and tissues, including neurons, vascular smooth muscle cells, T lymphocytes, dendritic cells, tumor cells, heart, liver, and pancreas. Because NOR1 was first identified in apoptotic neurons, it is functionally associated with the regulation of cell migration and the growth of neuronal synapses. In-depth studies have shown that NOR1 can be edited by the immediate early gene and functions as a transcription factor. NOR1 has been shown to be rapidly induced by a number of stimulants including growth factors, fatty acids, and neurotransmitters. Elevated NOR1 levels may be involved in a number of pathophysiological processes. These include regulation of cellular apoptosis and regeneration, neuron formation, contextual fearing memory, inflammation, vascular smooth muscle proliferation, insulin secretion, and tumor development, whereby NOR1 mediates the pathogenesis of numerous diseases such as cerebral ischemia, depression, post-traumatic stress disorder, atherosclerosis, abdominal aortic aneurysm, cardiac hypertrophy, diabetes, osteoarthritis, rheumatoid arthritis, and cancer. However, to date, comprehensive insights into the function of NOR1 are not available in sources published online. In this review, we provide a brief overview of the function and molecular and pharmacological regulation of NOR1 in various pathological or physiological conditions to advance the development of NOR1 as a novel target for disease treatment.

Guanxinping Tablets Inhibit ET-1-Induced Proliferation and Migration of MOVAS by Suppressing Activated PI3K/Akt/NF-κB Signaling Cascade

Background/Aim Abnormal proliferation and migration of vascular smooth muscle cells is one of the main causes of atherosclerosis (AS). Therefore, the suppression of abnormal proliferation and migration of smooth muscle cells are the important means for the prevention and inhibition of AS. The clinical effects of Guanxinping (GXP) tablets and preliminary clinical research on the topic have proved that GXP can effectively treat coronary heart disease, but its underlying mechanism remains unclear. This study aimed to confirm the inhibitory effect of GXP on the abnormal proliferation of mouse aortic vascular smooth muscle (MOVAS) cells and to explore the underlying mechanism. Methods MOVAS cells were divided into two major groups: physiological and pathological groups. In the physiological group, MOVAS cells were directly stimulated with GXP, whereas in the pathological group, the cells were stimulated by endothelin-1 (ET-1) before intervention by GXP. At the same time, atorvastatin calcium, which effectively inhibits the abnormal proliferation of MOVAS cells, was used in the negative control group. CCK8 assay, scratch test, ELISA, Western blotting, and immunofluorescence staining were performed to observe the proliferation and migration of MOVAS cells and the expression levels of related factors after drug intervention in each group. Results In the physiological group, GXP had no significant effect on the proliferation and migration of MOVAS cells and the related factors. In the pathological group, a high dose of GXP reduced the abnormal proliferation and migration of MOVAS cells. Further, it reduced the expression levels of PI3K; inhibited the phosphorylation of Akt (protein kinase B); upregulated IκB-α levels; prevented nuclear factor kappa B (NF-κB) from entering the nucleus; downregulated the expression of interleukin 6 (IL6), IL-1β, and iNOS; and upregulated the ratio of apoptosis-related factor Bax/Bcl-2. There was no significant difference between the high-dose GXP group and the atorvastatin calcium group (negative control group). Conclusion Our findings revealed that GXP was able to inhibit the proliferation and migration of MOVAS cells by regulating the PI3K/Akt/NF-κB pathway.

Abstract 371: The Role Of Scleraxis In Inducing Vascular Stiffness

Vascular dysfunction underlies numerous significant diseases including diabetes, atherosclerosis and hypertension. Vascular dysfunction can be a result of altered smooth muscle contraction/relaxation, and impaired endothelial cell function within the vessel wall. Vascular fibrosis involves an increase in the thickness of vessel wall. This contributes to either an increase in extracellular matrix (ECM) synthesis or induced vascular smooth muscle proliferation within the vessel wall, or both, causing stiffer vessels with impaired tone and reduced lumen diameter.Our lab identified the transcription factor scleraxis as a novel master regulator of fibrotic signaling in the myocardium, showing scleraxis is sufficient to induce fibroblast to myofibroblast phenotype conversion, a critical step in the development of fibrosis, and directly up-regulates ECM genes in cardiac fibroblasts. Angiotensin II (AngII) was reported to induce vascular fibrosis via activation of the transcription factor Smad3 in aortic vascular smooth muscle cells. Our lab has shown that Smad3 physically interacts with scleraxis, and critically requires scleraxis to drive TGFβ/Smad fibrotic signaling in cardiac fibroblasts.Our preliminary data has revealed that scleraxis is detectable in the arterial wall, and scleraxis expression is elevated in high pressure versus low pressure regions of vessels. Loss of scleraxis in the aortas of scleraxis knock-out mice reveals a discontinuation and disarrangement in the structure of vascular wall. We thus hypothesize that scleraxis is sufficient and necessary to induce vascular fibrosis.Pressure myography data reveals an increase in vascular stiffness and thickness of 3rd order mesenteric arteries of smooth muscle-specific scleraxis overexpression mice. Also, our data shows that vascular stiffness is significantly increased in AngII-induced scleraxis overexpression mice with a relative increase in telemetry blood pressure measurements and pulse wave velocity. Histological sections suggest a reduction of the translamellar ECM accumulations in AngII-induced scleraxis overexpression aortas. To summarize, scleraxis may contribute to vascular stiffness by inducing vascular smooth muscle proliferation.

The relationship between phosphodiesterase 4D gene polymorphism and coronary heart disease.

Coronary atherosclerotic heart disease is one of the most common heart diseases that seriously endanger human health. The study found that intracellular second messenger CAMP plays an important role in inhibiting the proliferation and migration of vascular smooth muscle and the local inflammatory response at the damaged vessel. Phosphodiesterase 4D (PDE4D) can specifically degrade cAMP. The purpose of this article is to investigate the relationship between phosphodiesterase 4D gene polymorphism and coronary heart disease and the effect of phosphodiesterase 4D gene polymorphism on cardiovascular, using polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) was used to detect 50 patients with coronary heart disease (ACS group) and 100 patients who were diagnosed with coronary artery disease by coronary angiography at the same time as the control group (NC group). The results of the study showed that the frequencies of AA, AG, and GG genotypes in 150 samples were 25.67%, 54.66%, and 22.67%, respectively, which was consistent with Hard Weber's law (X = 2.186, P = 0.101). The distribution of GG genotype (18% vs. 27%), AA + AG genotype (85% vs. 74%), G (57% vs. 55%), A (43% vs. 45 %) There was no statistically significant difference in allele frequency (P <0.05). From this, it can be seen that the rs918592 polymorphism of the PDE4D gene is not associated with coronary heart disease.