Smooth Muscle Research Articles

Long Non-Coding RNA Function in Smooth Muscle Cell Plasticity and Atherosclerosis.

In the healthy mature artery, vascular cells, including endothelial cells, smooth muscle cells (SMCs), and fibroblasts are organized in different layers, performing specific functions. SMCs located in the media are in a differentiated state and exhibit a contractile phenotype. However, in response to vascular injury within the intima, stimuli from activated endothelial cells and recruited inflammatory cells reach SMCs and induce a series of remodeling events in them, known as phenotypic switching. Indeed, SMCs retain a certain degree of plasticity and are able to transdifferentiate into other cell types that are crucial for both the formation and development of atherosclerotic lesions. Because of their highly cell-specific expression profiles and their widely recognized contribution to physiological and disease-related biological processes, long non-coding RNAs have received increasing attention in atherosclerosis research. Dynamic fluctuations in their expression have been implicated in the regulation of SMC identity. Sophisticated technologies are now available to allow researchers to access single-cell transcriptomes and study long non-coding RNA function with unprecedented precision. Here, we discuss the state of the art of long non-coding RNAs regulation of SMC phenotypic switching, describing the methodologies used to approach this issue and evaluating the therapeutic perspectives of exploiting long non-coding RNAs as targets in atherosclerosis.

Bone marrow-derived NGFR-positive dendritic cells regulate arterial remodeling.

It has been proposed that bone marrow contributes to the pathogenesis of arteriosclerosis. Nerve growth factor receptor (NGFR) is expressed in bone marrow stromal cells; it is also present in peripheral blood and ischemic coronary arteries. We hypothesized that bone marrow-derived NGFR-positive (NGFR+) cells regulate arterial remodeling. We found that human NGFR+ mononuclear cells (MNCs) in peripheral blood expressed markers for plasmacytoid dendritic cells (DCs) and were susceptible to apoptosis in response to proNGF secreted by activated arterial smooth muscle cells (SMCs). Bone marrow-specific depletion of NGFR+ cells increased neointimal formation following arterial ligation in mice. Bone marrow-derived NGFR+ cells accumulated in the neointima and underwent apoptosis. In contrast, in a bone marrow-specific NGFR-knockout model, SMCs occupied the neointima with augmented proliferation. NGFR+ cells in the neointima promoted mannose receptor C-type 1-positive anti-inflammatory macrophage accumulation and secreted anti-inflammatory IL-10, thereby inhibiting SMC proliferation in the neointima. In patients with acute coronary syndrome (ACS), NGFR+ peripheral MNCs increased after ACS onset. Multiple linear regression analysis showed that an insufficient increase in NGFR+ peripheral MNCs in ACS was an adjusted independent risk factor for 9-mo intimal progression of a nontargeted lesion. Taken together, these observations imply that bone marrow-derived NGFR+ DCs are suppressors of arteriosclerosis.NEW & NOTEWORTHY We propose a new concept of arterial remodeling after injury in which bone marrow-derived NGFR+ dendritic cells inhibit neointimal progression mediated by apoptosis. NGFR+ dendritic cells promote anti-inflammatory MRC1+ M2 macrophage accumulation and production of interleukin-10, inhibiting smooth muscle cell proliferation within the neointima. In a clinical study, insufficient mobilization of NGFR+ peripheral mononuclear cells in acute coronary syndrome was an independent risk factor for 9-mo nontargeted coronary intimal progression.

Nox1/PAK1 is required for angiotensin II-induced vascular inflammation and abdominal aortic aneurysm formation.

NADPH oxidase 1 (Nox1) is a major isoform of Nox in vascular smooth muscle cells (VSMCs). VSMC activation and extracellular matrix (ECM) remodelling induce abdominal aortic aneurysm (AAA). In this study, we aim to determine the role of Nox1 in the progression of AAA and explore the underling mechanism. ApoE-/-Nox1SMCko mice in which the Nox1 gene was smooth muscle cell (SMC)-specifically deleted in ApoE-/- background, were infused with angiotensin II (Ang II) for 28 days. We found the Nox1 deficiency reduced AAA formation and increased survival compared with ApoE-/-Nox1y/flox mice. Abdominal aortic ROS and monocyts/macrophages were reduced in the ApoE-/-Nox1SMCko mice after Ang II-infusion. The SMC-specific Nox1 deletion caused less elastin fragments and lower matrix metalloproteinase (MMP) activities in the abdominal aorta. Further, we found the Nox1 protein interacted with p21-activated kinase 1 (PAK1) in Ang II-stimulated VSMCs. The PAK1, controlled by Nox1/ROS, promoted VSMC proliferation, migration and differentiation; this is associated with increased activities of vimentin and cofilin, and cytoskeleton modulation. Moreover, we found that the Nox1/PAK1 activated the downstream MAPKs (ERK1/2, p38 and JNKs) and NF-κB, and upregulated Sp1-mediated MMP2 expression upon Ang II-stimulation. Finally, overexpression of PAK1 in the ApoE-/-Nox1SMCko mice increased vascular elastic fibre degradation, pro-inflammatory cytokine expression and AAA incidence. Therefore, we conclude that Nox1, together with PAK1, facilitates Ang II-induced VSMC activation, vascular inflammation and ECM remodelling, and thus potentiates the AAA formation.

543 Post-translational regulation of la ribonucleoprotein domain family member 6 by insulin-like growth factor-1 modulates collagen synthesis in smooth muscle cells

543 Post-translational regulation of la ribonucleoprotein domain family member 6 by insulin-like growth factor-1 modulates collagen synthesis in smooth muscle cells

Generation and characterization of three induced pluripotent stem cell lines for modeling coronary artery vasospasm.

Coronary artery vasospasm (CAV) is characterized by transient constriction of epicardial coronary arteries leading to angina. Its disease mechanisms are multifactorial but has centered mostly on endothelial dysfunction and smooth muscle hyperreactivity. To facilitate the investigation of these mechanisms in cell culture, we generated and characterized three induced pluripotent stem cell (iPSC) lines from patients with CAV. These lines demonstrated normal morphology and karyotypes, robust expression of pluripotency markers, and ability for tri-lineage differentiation. Further differentiation of these cell lines into endothelial and smooth muscle cells will allow mechanistic investigation of their relative contributions to CAV in cell culture.

Dose-responsive effects of endothelial cell-sourced exosomes on vascular cell proliferation and phenotype transition.

Endothelial cell-sourced exosomes are potential participants in the process of atherosclerosis, and their function is mainly affected by concentration. By studying the effects of exosome concentrations on vascular cells, atherosclerosis can be better intervened. In this study, exosomes with concentrations of 0, 0.07, 0.35, 1.75 and 8.75μg/mL were set to interact with endothelial cells, macrophages and smooth muscle cells respectively. The results suggested that EC-Exo altered vascular cells' proliferation, migration and nitric oxide release abilities, increasing with EC-Exo concentrate from 0 to 1.75μg/mL and varing with cell types at 8.75μg/mL. The effects of exosome on cells is dose-responsive，and endothelial cells-sourced exosome favors vascular repair within the concentration of 0.35-1.75μg/mL，showing potential for atherosclerosis regulation.

Pink1-Dependent Mitophagy in Vascular Smooth Muscle Cells: Implications for Arterial Constriction

Hypertension is a major global health issue, contributing to significant cardiovascular morbidity and mortality. Mitochondrial dysfunction, particularly through dysregulated mitophagy, has been implicated in the pathogenesis of hypertension. We wanted to find out the relationship between mitochondrial autophagy and changes in arterial smooth muscle cell tension and the molecular mechanism. Using RNA-seq analysis, we identified significant upregulation of autophagy-related genes, including Pink1, in the aortas of spontaneously hypertensive rats (SHR) compared to normotensive Wistar-Kyoto (WKY) rats. Further in vivo and in vitro studies revealed enhanced mitophagy, characterized by increased expression of Pink1 protein. Our experiments showed that knockdown of Pink1 expression by shRNA attenuated KPSS-induced vascular smooth muscle cells (VSMCs) contraction, suggesting that excessive mitophagy contributes to vascular dysfunction in hypertension. These findings highlight Pink1-mediated mitophagy as a crucial player in hypertensive vascular remodeling and present a potential therapeutic target for managing hypertension.

Hyperglycemia inhibits AAA expansion: examining the role of lysyl oxidase.

Abdominal aortic aneurysm (AAA) is a common, progressive, and potentially fatal dilation of the most distal aortic segment. Multiple studies with longitudinal follow-up of AAA have identified markedly slower progression among patients affected with diabetes. Understanding the molecular pathway responsible for the growth inhibition could have implications for therapy in nondiabetic patients with AAA. Toward this end, we investigated the effects of hyperglycemia in a murine model of AAA and a carefully monitored cohort of patients with AAA from the Noninvasive Treatment of AAA-Clinical Trial (NTA3CT). In mice with hyperglycemia, AAA growth was inhibited to a similar degree (∼30%) as seen in patients with diabetes. AAA growth correlated inversely to levels of hyperglycemia in mice and patients with AAA. Inhibiting lysyl oxidase (LOX) activity increases aneurysm growth and matrix degradation in this model. Hyperglycemia increased LOX concentration in aortic smooth muscle cells (SMCs) but not in murine AAA tissue. Inhibiting LOX activity completely blocked the growth-inhibitory effect of hyperglycemia. Lysyl oxidase-like 2 (LOXL2), the primary arterial isoform of LOX, is expressed in the same area as type IV collagen along the outer media in murine AAA tissue. There is a significant inverse correlation between LOXL2 and AAA growth rates in patients. Taken together, these studies suggest a role for LOXL2-mediated type IV collagen crosslinking in slowing AAA growth in the setting of hyperglycemia.NEW & NOTEWORTHY AAA grows slower in patients affected by diabetes. This growth inhibition is lost when the enzyme lysyl oxidase (LOX) is blocked in diabetic mice. The predominant arterial isoform of LOX, LOX-like 2 (LOXL2), overlaps with type IV collagen in the outer media of murine aneurysm tissue. Circulating LOXL2 correlates inversely with AAA growth in patients. Type IV collagen cross-linking by LOXL2 may play a role in the AAA growth inhibition associated with diabetes.

Improved porosity promotes reendothelialization and smooth muscle remodeling in decellularized tissue-engineered vascular grafts.

Decellularized tissue-engineered vascular grafts (dTEVGs) exhibit superior biocompatibility, anti-infection properties and repair potential, contributing to better patency and making them a more ideal choice for arteriovenous grafts (AVGs) in hemodialysis compared to chemically synthesized grafts. However, the unsatisfactory reendothelialization and smooth muscle remodeling of current dTEVGs limit their advantages. In this study, we investigated the use of elastase to improve the porosity of elastic fiber layers in dTEVGs, aiming to promote cell infiltration and achieve superior reendothelialization and smooth muscle remodeling. Our findings revealed that elastase treatment induced scattered cracks and holes in the elastic fiber layers of dTEVGs. Porous dTEVGs demonstrated increased cell infiltration in rat subcutaneous tissue. In the rat AVG models, mildly elastase-treated dTEVGs significantly improved cell infiltration and graft remodeling, including adequate smooth muscle cell (SMC) repopulation, impressive reendothelization and regeneration of the extracellular matrix, without stenosis, dilation or disintegration of the grafts. This study demonstrates that porous dTEVGs promote reendothelization, smooth muscle remodeling and extracellular matrix regeneration while retaining a stable graft structure, enhancing durability and puncture resistance in hemodialysis.

Multifunctional hyaluronic acid-based coating to direct vascular cell fate for enhanced vascular tissue healing.

Ensuring excellent anticoagulant, anti-inflammatory, and endothelialization properties in vascular stents through coating construction is crucial for their satisfactory performance post-implantation. In this study, we propose a cell-membrane mimetic multifunctional hyaluronic acid (HA)-based coating by combining the aminolyzed methacryloyloxyethyl phosphorylcholine (MPC) copolymer with oxidized hyaluronic acid (Ox-HA) through Schiff base reaction. Compared with traditional anti-fouling design, the composite coating present a stage-specific ability, which can resist the adhesion of blood components, while mediating vascular cell fate with the incorporation of HA. The coating exhibited promoted endothelial cell (EC) growth and inhibited the proliferation of smooth muscle cells (SMCs) by inducing a phenotype change. Besides, the multifunctional HA-based coating can mediate macrophages to a M2 phenotype. The coated stents were implanted in rabbits, and exhibited ideal capabilities in promoting endothelialization and inhibiting inflammation and restenosis in vivo, offering a potential approach to address multifunctionality for vascular implants.

Hydrogen sulfide attenuates disturbed flow-induced vascular remodeling by inhibiting LDHB-mediated autophagic flux

Disturbed flow (DF) plays a critical role in the development and progression of cardiovascular disease (CVD). Hydrogen sulfide (H2S) is involved in physiological processes within the cardiovascular system. However, its specific contribution to DF-induced vascular remodeling remains unclear. Here, we showed that the H2S donor, NaHS suppressed DF-induced vascular remodeling in mice. Further experiments demonstrated that NaHS inhibited the proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor-BB (PDGF), as well as the autophagy triggered by DF and PDGF. Mechanistically, RNA-Seq results revealed that NaHS counteracted the PDGF-induced upregulation of lactate dehydrogenase B (LDHB). Overexpression of LDHB abolished the protective effect of NaHS on DF-induced vascular remodeling. Furthermore, LDHB interacted with vacuolar-type proton ATPase catalytic subunit A (ATP6V1A), leading to lysosomal acidification, a process that was attenuated by NaHS treatment. The residues of leucine (Leu) 57 in ATP6V1A and serine (Ser) 269 in LDHB are critical for their interaction. Notably, the expression of LDHB was found to be elevated in vascular tissues from patients with abdominal aortic aneurysms (AAA) and thoracic aortic aneurysms (TAA). These data identify a molecular mechanism by which H2S attenuates DF-induced vascular remodeling by inhibiting LDHB and disrupting the interaction between LDHB and ATP6V1A, thereby impeding the autophagy process. Our findings provide insight that H2S or targeting LDHB has therapeutic potential for preventing and treating vascular remodeling.

Dimethyl fumarate is repurposed to ameliorate aortic aneurysm and dissection in mice.

Aortic aneurysm and dissection pose fatal threats but no effective drug therapies are available. Previous work has been directed to reduce risk factors or target key pathological events, but none of the translational efforts succeeds. Here, we attempt to repurpose dimethyl fumarate (DMF), an FDA-approved immunomodulatory drug for multiple sclerosis, for the treatment of aortic aneurysm and dissection. In three preclinical mouse models of abdominal aortic aneurysm (porcine pancreatic elastase perfusion or CaCl2 incubation) and thoracic aortic aneurysm and dissection (β-Aminopropionitrile feeding), DMF invariably protected mice from aneurysm growth, aortic dissection, rupture and death. Histological H&E and EVG staining demonstrated aortic architecture-preserving effects of DMF. Through transcriptome profiling and the connectivity map (CMap), we showed that DMF restored SRC-FAK signaling in aortic smooth muscle cells and increased collagen I turnover in the tunica media. Our work suggests the potential of DMF being repurposed for aortic aneurysm and dissection, and highlights the importance of SRC-FAK signaling in aortic homeostasis.

Application of subcutaneous extracellular matrix to prepare bilayer heparin-coated polycaprolactone/decellularized small-diameter vascular graft for tissue regeneration.

In clinical practice, the demand for functional small-diameter vascular grafts continues to increase. In this study, a decellularized aorta artery was inserted into a poly(caprolactone) (PCL) vascular scaffold for self-assembly in-vitro to create a hybrid scaffold. The hybrid scaffold was then implanted subcutaneously into the dorsal flanks and the subcutaneous extracellular matrix was applied for bilayer adhesion. After decellularization, the hybrid scaffold was coated with heparin to prepare a bilayer tissue-engineered vascular graft (BTEVG). The BTEVG exhibited enhanced biomechanical properties compared with those of decellularized tissue. The bilayer scaffold remained patent and displayed no expansion or aneurysm after implantation at 2months. Endothelial cell formation was observed on the neointimal surface. In the neointimal, decellularized tissue in the inner layer inhibited smooth muscle cells proliferation and neointimal hyperplasia of BTEVG. M2 macrophage cell proliferation in the neointimal may inhibit vascular smooth muscle cell proliferation. Although the PCL-H scaffold demonstrated calcification formation, no calcification was found in the BTEVG. Therefore, BTEVGs can be applied for rapid remodeling of small-diameter blood vessels.

Proteome of Pericytes from Retinal Vasculature of Diabetic Donor Eyes

Retinal pericytes (PCs) are contractile microvascular smooth muscle cells that wrap around the endothelial cells (ECs) maintaining intact retinal vasculature (RV) with a 1:1 ratio. Microvascular complications like Diabetic Retinopathy (DR) due to chronic Diabetes causes apoptotic loss of PCs followed by diminished vessel stability, EC apoptosis, and ischemia, leading to retinal angiogenesis, and eventually severe vision loss. This study aimed to analyze the proteins in PCs isolated from the RV of diabetic human donor eyes and compare them with remaining mixed population (MP) of retinal vascular cells. PCs and MP proteomes were analyzed using semi-quantitative proteomics. Proteins were extracted, quantified, and analyzed in duplicate using LC-MS/MS on a Tandem mass spectrometer. Overall, 42 PC and 27 MP proteins, with 19 shared proteins, were identified. Functional enrichment analysis indicated that PC proteins share common biological processes, such as negative regulation of fibrinolysis and vLDL particle remodeling, nitric oxide transport, phospholipid efflux, positive control over the clearance of apoptotic cells, chondrocyte proliferation, lipoprotein lipase activity, and oxidative stress-induced intrinsic atrophic signaling pathways. In the fold enrichment analysis, the PC proteins were associated with cholesterol metabolism, Complement and coagulant, ECM-receptor interaction, longevity regulating pathway, Peroxisome proliferator-activated receptors (PPAR), focal adhesion and PI3 Akt signaling pathways. Among the PC proteins, vitronectin, gelsolin, hornerin, apolipoprotein A1, C3, H, and complement Factors C3, C4, and C9 were identified as the most highly ranked proteins in diabetes. The identified unique proteins of retinal PC could prove beneficial as a therapeutic target in the management of DR.

Endothelium-independent vasorelaxant effects of Curcuma phaeocaulis essential oil and its representative compound isocurcumenol.

The rhizomes of Curcuma phaeocaulis Val. are a Rhizoma curcumae source in Chinese pharmacopoeia, and this traditional Chinese medicine has been extensively used in China to promote blood circulation and remove blood stasis. However, little is known regarding the vasodilatory effects and underlying mechanisms. This study investigated the vasorelaxant effects and mechanisms of C. phaeocaulis essential oil (CPEO) and its representative compound, isocurcumenol. The effects of CPEO and isocurcumenol on the contractile tension of isolated rat thoracic aortic rings in a resting state and a KCl or phenylephrine (PHE) preincubation state in the tissue organ bath system were studied. The potential vasodilatory mechanisms of CPEO and isocurcumenol were investigated using a series of experiments that included endothelium removal, CPEO and isocurcumenol preincubation, extracellular Ca2+-induced contraction and intracellular Ca2+ release, and incubation with various blockers. Laser confocal microscopy was used to evaluate the effect of isocurcumenol on the intracellular Ca2+ fluorescence intensity in A7r5 cells. The influence of isocurcumenol on the myosin light chain (MLC) protein expression and phosphorylation was determined using a Western blot assay. Furthermore, the whole-cell patch clamp technique was used to investigate the effect of isocurcumenol on voltage-dependent K⁺channel (Kv) current cells. CPEO (0.25-25mg/L) and isocurcumenol (0.25-25μM) exhibited concentration-dependent vasodilatory effects on endothelial intact vascular rings that were pre-contracted using KCl or PHE. These vasodilatory effects did not significantly change after the endothelium was removed. Notably, the vasodilatory effects of the CPEO and isocurcumenol were attenuated when preincubation was performed using with 4-aminopyridine (4-AP, a Kv channel blocker) or verapamil hydrochloride (an L-type calcium channel blocker). In the cell experiments, isocurcumenol suppressed an increase in the Ca2+ fluorescence intensity and inhibited the phosphorylation of the MLC protein in A7r5 cells. The results of the whole-cell patch clamp assay indicated that 25μM of isocurcumenol enhanced Kv channel currents. In this study, we confirmed that CPEO and isocurcumenol had significant endothelium-independent vasorelaxant effects. The underlying mechanism was attributed to the activation Kv channels and the suppression of L-type calcium channels. This resulted in a Ca2+ influx decrease in vascular smooth muscle cells and subsequent vascular contraction inhibition.

Breaking New Ground: Unraveling the USP1/ID3/E12/P21 Axis in Vascular Calcification

Vascular calcification (VC) poses significant challenges in cardiovascular health. This study employs single-cell transcriptome sequencing to dissect cellular dynamics in this process. We identify distinct cell subgroups, notably in vascular smooth muscle cells (VSMCs), and observe differences between calcified atherosclerotic cores and adjacent regions. Further exploration reveals ID3 as a key gene regulating VSMC function. In vitro experiments demonstrate ID3′s interaction with USP1 and E12, modulating cell proliferation and osteogenic differentiation. Animal models confirm the critical role of the USP1/ID3/E12/P21 axis in VC. This study sheds light on a novel regulatory mechanism, offering potential therapeutic targets.1.This study uses single-cell transcriptome to investigate vascular calcification in depth.2.This study successfully identifies cellular heterogeneity related to vascular calcification.3.This study reveals the crucial role of ID3 in vascular smooth muscle cell osteogenic differentiation.4.In vivo and in vitro experiments of this study demonstrate the regulatory role of the USP1/ID3/E12/P21 axis in calcification.5.This study provides potential molecular targets for the treatment of calcification-related diseases.

Electronic cigarette vape decreases nitric oxide bioavailability in vascular smooth muscle cells via increased cytoglobin-mediated metabolism.

Cytoglobin (Cygb) regulates vascular tone by modulating nitric oxide (NO) metabolism in vascular smooth muscle cells (VSMCs). In the presence of its cytochrome B5a (B5)/B5 reductase-isoform-3 (B5R) reducing system, Cygb controls NO metabolism via oxygen-dependent NO dioxygenation. Electronic cigarette (EC) use has been shown to induce vascular dysfunction and decrease NO bioavailability; however, the role of Cygb-mediated NO metabolism in the pathophysiology of this process has not been previously investigated. Therefore, we utilized aortic VSMCs with EC vape extract (ECE) exposure to elucidate the effects of EC vape constituents on NO degradation and alterations in the process of Cygb-mediated NO metabolism. VSMCs were exposed to ECE, either nicotine-free (ECEV) or nicotine-containing (ECEN), for various durations. NO decay rates were measured along with cellular expression of Cygb and its B5/B5R reducing system. Exposure to ECEV led to a much higher rate of NO consumption by VSMCs, with an even larger effect following ECEN exposure. With 4h of exposure, a modest increase in NO decay rate occurred that was followed by much higher increases with exposure times of 24-48h. This effect was paralleled by upregulation of Cygb and B5/B5R expression. siRNA-mediated knock-down of Cygb expression largely reversed this ECE-induced increase in NO metabolism rate. Thus, ECE exposure led to increased Cygb-mediated NO metabolism in VSMCs with diminished NO bioavailability, which in turn can play a key role in EC-induced vascular dysfunction.

Sildenafil Attenuates Persistent Pulmonary Hypertension of the Newborn via Inhibiting the Growth and Migration of Pulmonary Artery Smooth Muscle Cells.

Sildenafil, a selective phosphodiesterase 5 inhibitor, modulates vascular dysfunction, with hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) proliferation, migration, and invasion closely implicated in vascular remodeling in persistent pulmonary hypertension of the newborn (PPHN). This study aimed to assess sildenafil's protective effects against PPHN and elucidate underlying molecular pathways. Cell Counting Kit-8, wound healing, and Transwell assays evaluated rat PASMC proliferation, migration, and invasion under hypoxia. A rat PPHN model assessed sildenafil's impact on right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), and vascular remodeling. JAK2/STAT3 signaling was analyzed via Western blotting. Sildenafil significantly inhibited hypoxia-induced PASMC proliferation, migration, and invasion. In addition, sildenafil reduced RVSP, RVH, and vascular remodeling in PPHN. Further, sildenafil decreased JAK2 and STAT3 phosphorylation in hypoxia-exposed PASMCs and the PPHN rat model. The JAK2/STAT3 pathway agonist colivelin reversed sildenafil's suppressive effects on PASMC proliferation, migration, invasion, as well as RVSP, RVH, and vascular remodeling in PPHN. Sildenafil protects against PPHN by inhibiting PASMC proliferation, migration, and invasion via suppression of JAK2/STAT3 signaling, indicating its potential as a therapeutic target for PPHN and contributing to a more comprehensive understanding of PPHN pathogenesis.

WCN25-3772 Arntl inhibits osteogenic trans-differentiation of vascular smooth muscle cells during vascular calcification in chronic kidney disease

WCN25-3772 Arntl inhibits osteogenic trans-differentiation of vascular smooth muscle cells during vascular calcification in chronic kidney disease

Protective effects and bioinformatic analysis of narciclasine on vascular aging via cross-talk between inflammation and metabolism through inhibiting skeletal muscle-specific ceramide synthase 1.

The senescence of smooth muscle is one of the independent risk factors in atherosclerosis progression in which the vascular inflammation plays an important role on vascular dysfunction. This study is designed to explore the novel vascular aging biomarkers and screen the potential molecular interventional targets through bioinformatic analysis. Transcriptional analysis was conducted based on the GSE16487 open access database, which included 15 human vascular tissue samples from two groups: young group (≤ 60 years old, n = 8) and aged group (≥ 75 years old, n = 7). There were 275 differential expression genes (119 upregulated and 156 downregulated genes) with minimum 1.5-fold change between two groups. 9 genes were mainly participated in inflammation-related signaling pathways, in which narciclasine was validated as the most effective candidate for modulation the ceramide synthesis. In vitro and animal study demonstrated that narciclasine reversed vascular aging by inhibiting skeletal muscle-specific ceramide synthase 1 (CerS1), reducing the ceramide level derived from CerS1, and improving fat deposition and circulating glycolipid metabolism. Narciclasine attenuates vascular aging and modulates the cross-talk between inflammation and metabolism via inhibiting skeletal muscle-specific ceramide synthase 1.