RESUMEN
This study unveils the pivotal roles of taurine metabolic reprogramming and its implications in the development and progression of Abdominal Aortic Aneurysm (AAA). Leveraging an integrated approach that combines single-cell RNA sequencing (scRNA-seq) and Weighted Gene Co-expression Network Analysis (WGCNA), our research investigates the intricate transcriptional and gene expression dynamics crucial to AAA. Our findings uniquely link metabolic shifts to the integrity of the extracellular matrix (ECM) and the functionality of smooth muscle cells (SMCs), key elements in the pathology of AAA. Utilizing scRNA-seq data from a mouse model (GSE152583 dataset), we identified critical alterations in cellular composition during AAA progression, particularly highlighting shifts in fibroblasts and inflammatory cells. Concurrently, WGCNA of human AAA tissue samples has outlined distinct gene expression patterns correlated with disease severity and progression, offering comprehensive insights into both molecular and cellular disease mechanisms. Moreover, this study introduces innovative metabolic profiling techniques to identify differential metabolites in AAA, integrating extensive metabolomic analyses with pathway enrichment strategies. This novel approach has pinpointed potential biomarkers and therapeutic targets, notably within taurine metabolism pathways, crucial for crafting non-surgical interventions. By merging state-of-the-art bioinformatics with thorough molecular analysis, our study not only enhances the understanding of AAA's complex pathophysiology but also catalyzes the development of targeted therapeutic strategies. This research represents a significant advancement in the molecular characterization of AAA, with substantial implications for its future diagnosis and treatment strategies.
Asunto(s)
Aneurisma de la Aorta Abdominal , Progresión de la Enfermedad , Taurina , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/genética , Taurina/metabolismo , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Masculino , Análisis de la Célula Individual , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Metabolómica/métodos , Reprogramación MetabólicaRESUMEN
BACKGROUND: The interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive. METHODS AND RESULTS: To elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats. CONCLUSIONS: Imbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH.
Asunto(s)
Retardo del Crecimiento Fetal , GTP Fosfohidrolasas , Ratas Sprague-Dawley , Animales , Retardo del Crecimiento Fetal/metabolismo , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genética , Ratas , Femenino , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/patología , Hipertensión Arterial Pulmonar/fisiopatología , Dinámicas Mitocondriales/fisiología , Masculino , Células Cultivadas , Embarazo , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Modelos Animales de Enfermedad , Mitocondrias/metabolismo , Mitocondrias/patología , Animales Recién Nacidos , Proteínas MitocondrialesRESUMEN
BACKGROUND: The prevalence of vascular calcification (VC) in chronic kidney disease (CKD) patients remains substantial, but currently, there are no effective pharmaceutical therapies available. BRCA1/BRCA2-containing complex subunit 36 (BRCC36) has been implicated in osteoblast osteogenic conversion; however, its specific role in VC remains to be fully elucidated. The aim of this study was to investigate the role and underlying mechanisms of BRCC36 in VC. METHODS: The association between BRCC36 expression and VC was examined in radial arteries from patients with CKD, high-adenine-induced CKD mice, and vascular smooth muscle cells (VSMCs). Western blotting, real-time polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to analyse gene expression. Gain- and loss-of-function experiments were performed to comprehensively investigate the effects of BRCC36 on VC. Coimmunoprecipitation and TOPFlash luciferase assays were utilized to further investigate the regulatory effects of BRCC36 on the Wnt/ß-catenin pathway. RESULTS: BRCC36 expression was downregulated in human calcified radial arteries, calcified aortas from CKD mice, and calcified VSMCs. VSMC-specific BRCC36 overexpression alleviated calcium deposition in the vasculature, whereas BRCC36 depletion aggravated VC progression. Furthermore, BRCC36 inhibited the osteogenic differentiation of VSMCs in vitro. Rescue experiments revealed that BRCC36 exerts the protective effects on VC partly by regulating the Wnt/ß-catenin signalling pathway. Mechanistically, BRCC36 inhibited the Wnt/ß-catenin pathway by decreasing the K63-linked ubiquitination of ß-catenin. Additionally, pioglitazone attenuated VC partly through upregulating BRCC36 expression. CONCLUSIONS: Our research results emphasize the critical role of the BRCC36-ß-catenin axis in VC, suggesting that BRCC36 or ß-catenin may be promising therapeutic targets to prevent the progression of VC in CKD patients.
Asunto(s)
Ratones Endogámicos C57BL , Insuficiencia Renal Crónica , Ubiquitinación , Calcificación Vascular , Vía de Señalización Wnt , beta Catenina , Calcificación Vascular/metabolismo , Calcificación Vascular/patología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/complicaciones , Animales , beta Catenina/metabolismo , Humanos , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Ratones , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Osteogénesis , Persona de Mediana Edad , Diferenciación CelularRESUMEN
BACKGROUND: Visceral adipose tissue in individuals with obesity is an independent cardiovascular risk indicator. However, it remains unclear whether adipose tissue influences common cardiovascular diseases, such as atherosclerosis, through its secreted exosomes. METHODS: The exosomes secreted by adipose tissue from diet-induced obesity mice were isolated to examine their impact on the progression of atherosclerosis and the associated mechanism. Endothelial apoptosis and the proliferation and migration of vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque were evaluated. Statistical significance was analyzed using GraphPad Prism 9.0 with appropriate statistical tests. RESULTS: We demonstrate that adipose tissue-derived exosomes (AT-EX) exacerbate atherosclerosis progression by promoting endothelial apoptosis, proliferation, and migration of VSMCs within the plaque in vivo. MicroRNA-132/212 (miR-132/212) was detected within AT-EX cargo. Mechanistically, miR-132/212-enriched AT-EX exacerbates palmitate acid-induced endothelial apoptosis via targeting G protein subunit alpha 12 and enhances platelet-derived growth factor type BB-induced VSMC proliferation and migration by targeting phosphatase and tensin homolog in vitro. Importantly, melatonin decreases exosomal miR-132/212 levels, thereby mitigating the pro-atherosclerotic impact of AT-EX. CONCLUSION: These data uncover the pathological mechanism by which adipose tissue-derived exosomes regulate the progression of atherosclerosis and identify miR-132/212 as potential diagnostic and therapeutic targets for atherosclerosis.
Asunto(s)
Apoptosis , Aterosclerosis , Movimiento Celular , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Exosomas , Ratones Endogámicos C57BL , MicroARNs , Músculo Liso Vascular , Miocitos del Músculo Liso , Placa Aterosclerótica , Animales , MicroARNs/metabolismo , MicroARNs/genética , Exosomas/metabolismo , Exosomas/patología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/genética , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Músculo Liso Vascular/patología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Masculino , Transducción de Señal , Células Cultivadas , Obesidad/metabolismo , Obesidad/patología , Ratones Noqueados para ApoE , Células Endoteliales/metabolismo , Células Endoteliales/patología , Células Endoteliales/efectos de los fármacos , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/genética , Becaplermina/farmacología , Becaplermina/metabolismo , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Ratones , HumanosRESUMEN
BACKGROUND: Remodeling of vascular smooth muscle cells (VSMCs), as a pathological hallmark of cardiovascular diseases, is related to the molecular rewiring of Calcium signaling, which induces upregulation of stromal interaction molecule (STIM) proteins. This study analyzed the influence of STIM1 proteins on the remodeling of VSMCs in atherosclerosis (AS). METHODS: After oxidized low-density lipoprotein (ox-LDL) treatment and transfection, VSMC viability, migration, and invasion were separately measured using Cell Counting Kit-8, Scratch assay, and Transwell assay. An animal AS model was constructed, and histological analysis via hematoxylin-eosin staining was conducted on the aorta. RESULTS: Ox-LDL promoted expression of STIM1 and Orai calcium release-activated calcium modulator 1 (Orai1). STIM1 or Orai1 downregulation suppressed viability, migration, invasion, and phenotypic switching of ox-LDL-treated VSMCs, whereas STIM1 or Orai1 upregulation had opposite effects. Orai1 level was upregulated by STIM1 overexpression. Orai1 silencing reversed the effects of STIM1 overexpression in VSMCs. STIM1 deficiency alleviated AS and regulated expression of Orai1 and phenotypic switch-related factors in vivo. CONCLUSION: STIM1 deficiency suppresses viability, migration, invasion, and phenotypic switching of ox-LDL-induced VSMCs and alleviates AS by inhibiting Orai1.
Asunto(s)
Aterosclerosis , Movimiento Celular , Lipoproteínas LDL , Músculo Liso Vascular , Miocitos del Músculo Liso , Proteína ORAI1 , Molécula de Interacción Estromal 1 , Animales , Humanos , Masculino , Ratones , Aterosclerosis/patología , Aterosclerosis/metabolismo , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Lipoproteínas LDL/metabolismo , Músculo Liso Vascular/patología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Proteína ORAI1/metabolismo , Proteína ORAI1/genética , Proteína ORAI1/antagonistas & inhibidores , Molécula de Interacción Estromal 1/metabolismo , Molécula de Interacción Estromal 1/genética , Remodelación Vascular/efectos de los fármacosRESUMEN
Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize vascular diseases causing heart attack and stroke. Here we elucidate molecular determinants governing VSMC proliferation by reconstructing gene regulatory networks from single-cell transcriptomics and epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. We compared gene regulatory network rewiring between injury-responsive and nonresponsive VSMCs, which suggested shared transcription factors but differing target loci between VSMC states. Through in silico perturbation analysis, we identified and prioritized previously unrecognized regulators of proliferation, including RUNX1 and TIMP1. Moreover, we showed that the pioneer transcription factor RUNX1 increased VSMC responsiveness and that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signaling. Both RUNX1 and the TIMP1-CD74 axis were expressed in human VSMCs, showing low levels in normal arteries and increased expression in disease, suggesting clinical relevance and potential as vascular disease targets.
Asunto(s)
Proliferación Celular , Redes Reguladoras de Genes , Músculo Liso Vascular , Miocitos del Músculo Liso , Factor de Transcripción STAT3 , Inhibidor Tisular de Metaloproteinasa-1 , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Músculo Liso Vascular/citología , Humanos , Proliferación Celular/genética , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Transducción de Señal/genética , Células Cultivadas , Análisis de la Célula Individual , Epigénesis Genética , Transcriptoma , Animales , Subunidad alfa 2 del Factor de Unión al Sitio PrincipalRESUMEN
Drugs that lower plasma apolipoprotein B (ApoB)-containing lipoproteins are central to treating advanced atherosclerosis and provide partial protection against clinical events. Previous research showed that lowering ApoB-containing lipoproteins stops plaque inflammation, but how these drugs affect the heterogeneous population of plaque cells derived from smooth muscle cells (SMCs) is unknown. SMC-derived cells are the main cellular component of atherosclerotic lesions and the source of structural components that determine the size of plaques and their propensity to rupture and trigger thrombosis, the proximate cause of heart attack and stroke. Using lineage tracing and single-cell techniques to investigate the full SMC-derived cellular compartment in progressing and regressing plaques in mice, here we show that lowering ApoB-containing lipoproteins reduces nuclear factor kappa-light-chain-enhancer of activated B cells signaling in SMC-derived fibromyocytes and chondromyocytes and leads to depletion of these abundant cell types from plaques. These results uncover an important mechanism through which cholesterol-lowering drugs can achieve plaque regression.
Asunto(s)
Aterosclerosis , Modelos Animales de Enfermedad , Miocitos del Músculo Liso , Placa Aterosclerótica , Animales , Placa Aterosclerótica/patología , Placa Aterosclerótica/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/metabolismo , Aterosclerosis/patología , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Condrocitos/efectos de los fármacos , Condrocitos/patología , Condrocitos/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Anticolesterolemiantes/farmacología , Anticolesterolemiantes/uso terapéutico , Masculino , Colesterol/metabolismo , Colesterol/sangre , Ratones , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/metabolismo , Análisis de la Célula Individual , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Músculo Liso Vascular/metabolismo , FN-kappa B/metabolismoRESUMEN
Smooth muscle cell (SMC) phenotypic modulation, primarily driven by PDGFRß signaling, is implicated in occlusive cardiovascular diseases. However, the promotive and restrictive regulation mechanism of PDGFRß and the role of protein tyrosine phosphatase non-receptor type 14 (PTPN14) in neointimal hyperplasia remain unclear. Our study observes a marked upregulation of PTPN14 in SMCs during neointimal hyperplasia. PTPN14 overexpression exacerbates neointimal hyperplasia in a phosphatase activity-dependent manner, while SMC-specific deficiency of PTPN14 mitigates this process in mice. RNA-seq indicates that PTPN14 deficiency inhibits PDGFRß signaling-induced SMC phenotypic modulation. Moreover, PTPN14 interacts with intracellular region of PDGFRß and mediates its dephosphorylation on Y692 site. Phosphorylation of PDGFRßY692 negatively regulates PDGFRß signaling activation. The levels of both PTPN14 and phospho-PDGFRßY692 are correlated with the degree of stenosis in human coronary arteries. Our findings suggest that PTPN14 serves as a critical modulator of SMCs, promoting neointimal hyperplasia. PDGFRßY692, dephosphorylated by PTPN14, acts as a self-inhibitory site for controlling PDGFRß activation.
Asunto(s)
Hiperplasia , Miocitos del Músculo Liso , Neointima , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Transducción de Señal , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Animales , Hiperplasia/metabolismo , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Humanos , Neointima/metabolismo , Neointima/patología , Ratones , Fosforilación , Masculino , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Vasos Coronarios/patología , Vasos Coronarios/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologíaRESUMEN
Induction of resistin-like molecule ß (Relm-ß) and mitofusin 2 (MFN2) mediated aberrant mitochondrial fission have been found to be involved in the pathogenesis of pulmonary arterial hypertension (PAH). However, the molecular mechanisms underlying Relm-ß regulation of MFN2 therefore mitochondrial fission remain unclear. This study aims to address these issues. Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. The results showed that Relm-ß promoted cells proliferation in PASMCs, this was accompanied with the upregulation of USP18, Twist1 and miR-214, and downregulation of MFN2. We found that Relm-ß increased USP18 expression which in turn raised Twist1 by suppressing its proteasome degradation. Elevation of Twist1 increased miR-214 expression and then reduced MFN2 expression and mitochondrial fragmentation leading to PASMCs proliferation. In vivo study, we confirmed that Relm-ß was elevated in MCT-induced PAH rat model, and USP18/Twist1/miR-214/MFN2 axis was altered similar as in vitro. Targeting this cascade by Relm-ß receptor inhibitor Calhex231, proteasome inhibitor MG-132, Twist1 inhibitor Harmine or miR-214 antagomiR prevented the development of pulmonary vascular remodeling and therefore PAH in MCT-treated rats. In conclusion, we demonstrate that Relm-ß promotes PASMCs proliferation and vascular remodeling by activating USP18/Twist1/miR-214 dependent MFN2 reduction and mitochondrial fission, suggesting that this signaling pathway might be a promising target for management of PAH.
Asunto(s)
Proliferación Celular , GTP Fosfohidrolasas , MicroARNs , Mitocondrias , Ratas Sprague-Dawley , Transducción de Señal , Proteína 1 Relacionada con Twist , Ubiquitina Tiolesterasa , Animales , Masculino , Ratas , Proliferación Celular/efectos de los fármacos , GTP Fosfohidrolasas/metabolismo , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales , Monocrotalina/toxicidad , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/patología , Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Arteria Pulmonar/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína 1 Relacionada con Twist/metabolismo , Proteína 1 Relacionada con Twist/genética , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genéticaRESUMEN
Vascular smooth muscle cells (VSMCs) play a critical role in maintaining vascular integrity. VSMC dysfunction leads to numerous vascular diseases. Adenosine deaminases acting on RNA 1 (ADAR1), an RNA editing enzyme, has shown both RNA editing and non-editing functions. Global deletion of ADAR1 causes embryonic lethality, but the phenotype of homozygous ADAR1 deletion specifically in SMCs (ADAR1sm-/-) remains to be determined. By crossing ADAR1fl/fl mice with Myh11-CreERT2 mice followed by Tamoxifen induction, we found that ADAR1sm-/- leads to lethality in adult mice 14 days after the induction. Gross examination revealed extensive hemorrhage and detrimental vascular damage in different organs. Histological analyses revealed destruction of artery structural integrity with detachment of elastin laminae from VSMCs in ADAR1sm-/- aortas. Furthermore, ADAR1sm-/- resulted in severe VSMC apoptosis and mitochondrial dysfunction. RNA sequencing analyses of ADAR1sm-/- aorta segments demonstrated profound transcriptional alteration of genes impacting vascular health including a decrease in fibrillin-1 expression. More importantly, ADAR1sm-/- disrupts the elastin and fibrillin-1 interaction, a molecular event essential for artery structure. Our results indicate that ADAR1 plays a critical role in maintaining SMC survival and vascular stability and resilience.
Asunto(s)
Adenosina Desaminasa , Homeostasis , Músculo Liso Vascular , Miocitos del Músculo Liso , Animales , Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Ratones , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Aorta/metabolismo , Aorta/patología , Apoptosis/genética , Fibrilina-1/genética , Fibrilina-1/metabolismo , Elastina/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BL , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genéticaRESUMEN
Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disease characterized by increased pulmonary vascular resistance because of vascular remodeling and vasoconstriction. Subsequently, PAH leads to right ventricular hypertrophy and heart failure. Cell death mechanisms play a significant role in development and tissue homeostasis, and regulate the balance between cell proliferation and differentiation. Several basic and clinical studies have demonstrated that multiple mechanisms of cell death, including pyroptosis, apoptosis, autophagy, ferroptosis, anoikis, parthanatos, and senescence, are closely linked with the pathogenesis of PAH. This review summarizes different cell death mechanisms involved in the death of pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs), the primary target cells in PAH. This review summarizes the role of these cell death mechanisms, associated signaling pathways, unique effector molecules, and various pro-survival or reprogramming mechanisms. The aim of this review is to summarize the currently known molecular mechanisms underlying PAH. Further investigations of the cell death mechanisms may unravel new avenues for the prevention and treatment of PAH.
Asunto(s)
Células Endoteliales , Miocitos del Músculo Liso , Hipertensión Arterial Pulmonar , Arteria Pulmonar , Transducción de Señal , Humanos , Células Endoteliales/patología , Miocitos del Músculo Liso/patología , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/patología , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Muerte Celular , Animales , Apoptosis , Autofagia/fisiología , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatologíaRESUMEN
ABSTRACT: Aneurysms are localized dilations of blood vessels, which can expand to 50% of the original diameter. They are more common in cardiovascular and cerebrovascular vessels. Rupture is one of the most dangerous complications. The pathophysiology of aneurysms is complex and diverse, often associated with progressive vessel wall dysfunction resulting from vascular smooth muscle cell death and abnormal extracellular matrix synthesis and degradation. Multiple studies have shown that long noncoding RNAs (lncRNAs) play a significant role in the progression of cardiovascular and cerebrovascular diseases. Therefore, it is necessary to find and summarize them. LncRNAs control gene expression and disease progression by regulating target mRNA or miRNA and are biomarkers for the diagnosis and prognosis of aneurysmal cardiovascular and cerebrovascular diseases. This review explores the role, mechanism, and clinical value of lncRNAs in aneurysms, providing new insights for a deeper understanding of the pathogenesis of cardiovascular and cerebrovascular aneurysms.
Asunto(s)
Aneurisma Intracraneal , Músculo Liso Vascular , Miocitos del Músculo Liso , Fenotipo , ARN Largo no Codificante , Humanos , Músculo Liso Vascular/patología , Músculo Liso Vascular/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Aneurisma Intracraneal/genética , Aneurisma Intracraneal/patología , Aneurisma Intracraneal/metabolismo , Aneurisma Intracraneal/fisiopatología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Animales , Regulación de la Expresión Génica , Aneurisma/genética , Aneurisma/patología , Aneurisma/metabolismo , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Transducción de SeñalRESUMEN
BACKGROUND: Abdominal aortic aneurysm (AAA) is a complex vascular disorder characterized by the progressive dilation of the abdominal aorta, with a high risk of rupture and mortality. Understanding the cellular interactions and molecular mechanisms underlying AAA development is critical for identifying potential therapeutic targets. METHODS: This study utilized datasets GSE197748, GSE164678 and GSE183464 from the GEO database, encompassing bulk and single-cell RNA sequencing data from AAA and control samples. We performed principal component analysis, differential expression analysis, and functional enrichment analysis to identify key pathways involved in AAA. Cell-cell interactions were investigated using CellPhoneDB, focusing on fibroblasts, vascular smooth muscle cells (VSMCs), and macrophages. We further validated our findings using a mouse model of AAA induced by porcine pancreatic enzyme infusion, followed by gene expression analysis and co-immunoprecipitation experiments. RESULTS: Our analysis revealed significant alterations in gene expression profiles between AAA and control samples, with a pronounced immune response and cell adhesion pathways being implicated. Single-cell RNA sequencing data highlighted an increased proportion of pro-inflammatory macrophages, along with changes in the composition of fibroblasts and VSMCs in AAA. CellPhoneDB analysis identified critical ligand-receptor interactions, notably collagen type I alpha 1 chain (COL1A1)/COL1A2-CD18 and thrombospondin 1 (THBS1)-CD3, suggesting complex communication networks between fibroblasts and VSMCs. In vivo experiments confirmed the upregulation of these genes in AAA mice and demonstrated the functional interaction between COL1A1/COL1A2 and CD18. CONCLUSION: The interaction between fibroblasts and VSMCs, mediated by specific ligand-receptor pairs such as COL1A1/COL1A2-CD18 and THBS1-CD3, plays a pivotal role in AAA pathogenesis.
Asunto(s)
Aneurisma de la Aorta Abdominal , Músculo Liso Vascular , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/metabolismo , Animales , Ratones , Análisis de la Célula Individual/métodos , Humanos , Análisis de Secuencia de ARN/métodos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Macrófagos/metabolismo , Progresión de la Enfermedad , Fibroblastos/metabolismo , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Perfilación de la Expresión Génica/métodos , Comunicación Celular/genética , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismoRESUMEN
BACKGROUND: Due to a special hemodynamic feature, pulmonary vascular disease in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) has two stages: reversible and irreversible. So far, the mechanism involved in the transition from reversible to irreversible stage is elusive. Moreover, no recognized and reliable assessments to distinguish these two stages are available. Furthermore, we found that compared with control and reversible PAH, thrombospondin-4 (THBS4) was significantly upregulated in irreversible group by bioinformatic analysis. Hence, we further verify and investigate the expression and role of THBS4 in PAH-CHD. METHODS: We established the monocrotaline plus aorto-cava shunt-induced (MCT-AV) rat model. We measured the expression of THBS4 in lung tissues from MCT-AV rats. Double immunofluorescence staining of lung tissue for THBS4 and α-SMA (biomarker of smooth muscle cells) or vWF (biomarker of endothelial cells) to identify the location of THBS4 in the pulmonary artery. Primary pulmonary artery smooth muscle cells (PASMCs) were cultivated, identified, and used in this study. THBS4 was inhibited and overexpressed by siRNA and plasmid, respectively, to explore the effect of THBS4 on phenotype transformation, proliferation, apoptosis, and migration of PASMCs. The effect of THBS4 on pulmonary vascular remodeling was evaluated in vivo by adeno-associated virus which suppressed THBS4 expression. Circulating level of THBS4 in patients with PAH-CHD was measured by ELISA. RESULTS: THBS4 was upregulated in the lung tissues of MCT-AV rats, and was further upregulated in severe pulmonary vascular lesions. And THBS4 was expressed mainly in PASMCs. When THBS4 was inhibited, contractile markers α-SMA and MYH11 were upregulated, while the proliferative marker PCNA was decreased, the endothelial-mensenchymal transition marker N-cad was downregulated, proapototic marker BAX was increased. Additionally, proliferation and migration of PASMCs was inhibited and apoptosis was increased. Conversely, THBS4 overexpression resulted in opposite effects. And the impact of THBS4 on PASMCs was probably achieved through the regulation of the PI3K/AKT pathway. THBS4 suppression attenuated pulmonary vascular remodeling. Furthermore, compared with patients with simple congenital heart disease and mild PAH-CHD, the circulating level of THBS4 was higher in patients with severe PAH-CHD. CONCLUSIONS: THBS4 is a promising biomarker to distinguish reversible from irreversible PAH-CHD before repairing the shunt. THBS4 is a potential treatment target in PAH-CHD, especially in irreversible stage.
Asunto(s)
Cardiopatías Congénitas , Hipertensión Arterial Pulmonar , Ratas Sprague-Dawley , Trombospondinas , Animales , Humanos , Masculino , Ratas , Células Cultivadas , Cardiopatías Congénitas/metabolismo , Cardiopatías Congénitas/complicaciones , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/patología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/patología , Trombospondinas/metabolismo , Trombospondinas/biosíntesis , Trombospondinas/genéticaRESUMEN
Neoatherosclerosis (NA) within stents has become an important clinical problem after coronary artery stent implantation. In-stent restenosis and in-stent thrombosis are the two major complications following coronary stent placement and seriously affect patient prognosis. As the common pathological basis of these two complications, NA plaques, unlike native atherosclerotic plaques, often grow around residual oxidized lipids and stent struts. The main components are foam cells formed by vascular smooth muscle cells (VSMCs) engulfing oxidized lipids at lipid residue sites. Current research mainly focuses on optical coherence tomography (OCT) and intravascular ultrasound (IVUS), but the specific pathogenesis of NA is still unclear. A thorough understanding of the pathogenesis and pathological features of NA provides a theoretical basis for clinical treatment. This article reviews the previous research of our research group and the current situation of domestic and foreign research.
Asunto(s)
Tomografía de Coherencia Óptica , Humanos , Reestenosis Coronaria/etiología , Reestenosis Coronaria/diagnóstico por imagen , Reestenosis Coronaria/terapia , Reestenosis Coronaria/patología , Aterosclerosis/terapia , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/metabolismo , Aterosclerosis/patología , Placa Aterosclerótica/patología , Placa Aterosclerótica/terapia , Placa Aterosclerótica/diagnóstico por imagen , Stents/efectos adversos , Músculo Liso Vascular/patología , Músculo Liso Vascular/metabolismo , Ultrasonografía Intervencional/métodos , Enfermedad de la Arteria Coronaria/terapia , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/etiología , Enfermedad de la Arteria Coronaria/patología , Células Espumosas/patología , Células Espumosas/metabolismo , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/metabolismoRESUMEN
The proliferative and migratory abilities of vascular smooth muscle cells (VSMCs) play a crucial role in neointima formation following vascular injury. Skp2 facilitates proliferation and migration in cells through cell cycle regulation, presenting an important therapeutic target for atherosclerosis, pulmonary hypertension, and vascular restenosis. This study aimed to identify a natural product capable of inhibiting neointima formation post vascular injury. Here, we demonstrate that troxerutin, a flavonoid, significantly reduced viability and downregulated Skp2 in VSMCs. Moreover, troxerutin exhibited anti-proliferative effects on VSMCs and mitigated neointima formation. These findings collectively elucidate the intrinsic mechanism of troxerutin in treating atherosclerosis, pulmonary hypertension, and vascular restenosis by targeting the E3-linked enzyme Skp2.
Asunto(s)
Proliferación Celular , Hidroxietilrutósido , Músculo Liso Vascular , Neointima , Proteínas Quinasas Asociadas a Fase-S , Hidroxietilrutósido/análogos & derivados , Hidroxietilrutósido/farmacología , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Proteínas Quinasas Asociadas a Fase-S/antagonistas & inhibidores , Neointima/tratamiento farmacológico , Neointima/patología , Neointima/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/citología , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Proteolisis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Movimiento Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , RatasRESUMEN
BACKGROUND: High levels of lactate are positively associated with prognosis and mortality in pulmonary hypertension (PH). Lactate dehydrogenase A (LDHA) is a key enzyme for the production of lactate. This study is undertaken to investigate the role and molecular mechanisms of lactate and LDHA in PH. METHODS: Lactate levels were measured by a lactate assay kit. LDHA expression and localization were detected by western blot and Immunofluorescence. Proliferation and migration were determined by CCK8, western blot, EdU assay and scratch-wound assay. The right heart catheterization and right heart ultrasound were measured to evaluate cardiopulmonary function. RESULTS: In vitro, we found that lactate promoted proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) in an LDHA-dependent manner. In vivo, we found that LDHA knockdown reduced lactate overaccumulation in the lungs of mice exposed to hypoxia. Furthermore, LDHA knockdown ameliorated hypoxia-induced vascular remodeling and right ventricular dysfunction. In addition, the activation of Akt signaling by hypoxia was suppressed by LDHA knockdown both in vivo and in vitro. The overexpression of Akt reversed the inhibitory effect of LDHA knockdown on proliferation in PASMCs under hypoxia. Finally, LDHA inhibitor attenuated vascular remodeling and right ventricular dysfunction in Sugen/hypoxia mouse PH model, Monocrotaline (MCT)-induced rat PH model and chronic hypoxia-induced mouse PH model. CONCLUSIONS: Thus, LDHA-mediated lactate production promotes pulmonary vascular remodeling in PH by activating Akt signaling pathway, suggesting the potential role of LDHA in regulating the metabolic reprogramming and vascular remodeling in PH.
Asunto(s)
Proliferación Celular , Hipertensión Pulmonar , L-Lactato Deshidrogenasa , Lactato Deshidrogenasa 5 , Ácido Láctico , Ratones Endogámicos C57BL , Arteria Pulmonar , Remodelación Vascular , Animales , Humanos , Masculino , Ratones , Ratas , Hipoxia de la Célula , Movimiento Celular , Técnicas de Silenciamiento del Gen , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipoxia/complicaciones , Hipoxia/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Lactato Deshidrogenasa 5/metabolismo , Ácido Láctico/metabolismo , Pulmón/patología , Pulmón/irrigación sanguínea , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Arteria Pulmonar/patología , Arteria Pulmonar/metabolismo , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
Human aortic vascular smooth muscle cells (HA-VSMCs) play vital roles in the pathogenesis of vascular diseases, including Atherosclerosis (AS). Circular RNAs (circRNAs) have been reported to regulate the biological functions of HA-VSMCs. Therefore, this study aimed to explore the role and mechanism of hsa_circRNA_102353 (circ_0007765) in platelet-derived growth factor-BB (PDGF-BB)-induced HA-VSMCs. Circ_0007765, microRNA-654-3p (miR-654-3p), and Fibroblast Growth Factor Receptor Substrate 2 (FRS2) expression were measured using real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferative ability, invasion, and migration were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), Transwell, and wound healing assays. CyclinD1, MMP2, and FRS2 protein levels were assessed using a Western blot assay. Binding between miR-654-3p and circ_0007765 or FRS2 was predicted by Circinteractome or TargetScan, and verified using dual-luciferase reporter and RNA pull-down assays. PDGF-BB induced HA-VSMC proliferation, invasion, and migration. Circ_0007765 and FRS2 expression levels were increased in PDGF-BB-treated HA-VSMCs, and the miR-654-3p level was reduced. Moreover, circ_0007765 absence hindered PDGF-BB-induced HA-VSMC proliferation, invasion, and migration in vitro. At the molecular level, circ_0007765 increased FRS2 expression by acting as a sponge for miR-654-3p. Our findings revealed that circ_0007765 boosted PDGF-BB-induced HA-VSMC proliferation and migration through elevating FRS2 expression via adsorbing miR-654-3p, providing a feasible therapeutic strategy for AS.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Aterosclerosis , Becaplermina , Movimiento Celular , Proliferación Celular , Proteínas de la Membrana , MicroARNs , Músculo Liso Vascular , Miocitos del Músculo Liso , ARN Circular , Transducción de Señal , Humanos , Músculo Liso Vascular/patología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , ARN Circular/metabolismo , ARN Circular/genética , Becaplermina/farmacología , Movimiento Celular/efectos de los fármacos , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , MicroARNs/metabolismo , MicroARNs/genética , Aterosclerosis/patología , Aterosclerosis/metabolismo , Aterosclerosis/genética , Células Cultivadas , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Aorta/patología , Aorta/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Regulación de la Expresión Génica , Ratones Noqueados para ApoE , AnimalesRESUMEN
Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy that, if not promptly treated, culminates in right heart failure. Therefore, pre-clinical studies are needed to support and optimize therapeutic approaches of PAH. Here, we explore a prospective function of sevoflurane in experimental PAH through regulating TRAF6. Monocrotaline (MCT)-induced PAH rats were subjected to sevoflurane inhalation and intratracheal instillation of lentivirus overexpressing TRAF6. Platelet-derived growth factor (PDGF)-treated pulmonary artery smooth muscle cells (PASMCs) were exposed to sevoflurane and genetically manipulated for TRAF6 overexpression. It was found that MCT and PDGF challenge upregulated the levels of TRAF6 in rat lung tissues and PASMCs, but sevoflurane treatment led to reduced TRAF6 expression. Sevoflurane inhalation in MCT-induced rats resulted in alleviative pulmonary vascular remodeling, mitigated right ventricular dysfunction and hypertrophy, improved mitochondrial function and dynamics, and inactivation of NF-κB pathway. In vitro studies confirmed that exposure to sevoflurane repressed PDGF-induced proliferation, migration, and phenotype switching of PASMCs, and suppressed mitochondrial dysfunction and NF-κB activation in PDGF-stimulated PASMCs. The beneficial impact of sevoflurane on pathological changes of lung and cell phenotype of PASMCs were reversed by overexpression of TRAF6. In summary, our study suggested the protective properties of sevoflurane in targeting PAH by downregulating TRAF6 expression, providing a novel avenue for the management of PAH.
Asunto(s)
Regulación hacia Abajo , Miocitos del Músculo Liso , Hipertensión Arterial Pulmonar , Arteria Pulmonar , Ratas Sprague-Dawley , Sevoflurano , Factor 6 Asociado a Receptor de TNF , Animales , Sevoflurano/farmacología , Sevoflurano/toxicidad , Regulación hacia Abajo/efectos de los fármacos , Ratas , Masculino , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/genética , Hipertensión Arterial Pulmonar/inducido químicamente , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Arteria Pulmonar/metabolismo , Monocrotalina/toxicidad , FN-kappa B/metabolismo , Proliferación Celular/efectos de los fármacos , Remodelación Vascular/efectos de los fármacos , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Células CultivadasRESUMEN
The phenotypic switch of vascular smooth cells (VSMCs) from a contractile to a synthetic state is associated with the development and progression of aortic aneurysm (AA). However, the mechanism underlying this process remains unclear. In this issue of the JCI, Song et al. identified SLC44A2 as a regulator of the phenotypic switch in VSMCs. Inhibition of SLC44A2 facilitated the switch to the synthetic state, contributing to the development of AA. Mechanistically, SLC44A2 interacted with NRP1 and ITGB3 to activate the TGF-ß/SMAD signaling pathway, resulting in VSMCs with a contractile phenotype. Furthermore, VSMC-specific SLC44A2 overexpression by genetic or pharmacological manipulation reduced AA in mouse models. These findings suggest the potential of targeting the SLC44A2 signaling pathway for AA prevention and treatment.