Potassium dehydroandrographolide succinate regulates the MyD88/CDH13 signaling pathway to enhance vascular injury-induced pathological vascular remodeling.

Pathological vascular remodeling is a hallmark of various vascular diseases. Previous research has established the significance of andrographolide in maintaining gastric vascular homeostasis and its pivotal role in modulating endothelial barrier dysfunction, which leads to pathological vascular remodeling. Potassium dehydroandrographolide succinate (PDA), a derivative of andrographolide, has been clinically utilized in the treatment of inflammatory diseases precipitated by viral infections. This study investigates the potential of PDA in regulating pathological vascular remodeling. The effect of PDA on vascular remodeling was assessed through the complete ligation of the carotid artery in C57BL/6 mice. Experimental approaches, including rat aortic primary smooth muscle cell culture, flow cytometry, bromodeoxyuridine (BrdU) incorporation assay, Boyden chamber cell migration assay, spheroid sprouting assay, and Matrigel-based tube formation assay, were employed to evaluate the influence of PDA on the proliferation and motility of smooth muscle cells (SMCs). Molecular docking simulations and co-immunoprecipitation assays were conducted to examine protein interactions. The results revealed that PDA exacerbates vascular injury-induced pathological remodeling, as evidenced by enhanced neointima formation. PDA treatment significantly increased the proliferation and migration of SMCs. Further mechanistic studies disclosed that PDA upregulated myeloid differentiation factor 88 (MyD88) expression in SMCs and interacted with T-cadherin (CDH13). This interaction augmented proliferation, migration, and extracellular matrix deposition, culminating in pathological vascular remodeling. Our findings underscore the critical role of PDA in the regulation of pathological vascular remodeling, mediated through the MyD88/CDH13 signaling pathway.

Paeonol Promotes Reendothelialization After Vascular Injury Through Activation of c-Myc/VEGFR2 Signaling Pathway.

Purpose: Dysfunction of endothelium is associated with multiple pathological vascular diseases. However, how to regulate reendothelialization after vascular injury is not well defined. This study aims to determine whether and how Paeonol controls reendothelialization following artery injury. Methods: The endothelium of murine carotid artery was denuded by catheter guide wires injury. H&E staining and IF staining were performed to determine whether Paeonol is critical for reendothelialization. BRDU Incorporation Assay, Boyden Chamber Migration Assay, Tube Formation Assay, and Spheroid Sprouting Assay were used to investigate whether Paeonol is involved in regulating proliferation and migration of endothelial cells. The underlying mechanism of how Paeonol regulates reendothelialization was determined by Molecular docking simulation and CO-IP Assay. Results: Paeonol treatment significantly inhibits neointima formation in carotid artery ligation model by promoting proliferation and migration of endothelial cells. Mechanistically, Paeonol enhances c-Myc expression, consequently interacts with VEGFR2 results in activating VEGF signaling pathway, and eventually promotes reendothelialization after vascular injury. Conclusion: Our data demonstrated that Paeonol plays a critical role in regulating vascular reendothelialization, which may be therapeutically used for treatment of pathological vascular diseases.

Mir-485-5p on the Morphology and Function of Cardiovascular System.

Cardiovascular disease is a global problem that seriously endangers human health and life. At present, hypertension is considered to be a polygenic disease caused by the interaction of environmental factors and genetic factors. Various environmental factors have been proved to promote the occurrence and development of cardiovascular disease. MicroRNA (miR), as an essential gene regulatory factor in vivo, has been confirmed to participate in the regulation of many cell pathways, and its abnormal expression is closely related to a variety of human diseases. MiR-485-5p is located at 7q22.1, which has been proved to play an essential role in the tumor and cardiovascular system. Therefore, this paper discussed the mechanism of miR-485-5p on the morphology and function of the cardiovascular system. It is believed that miR-485-5p will impact the morphology and function of the cardiovascular system. Therefore, in the current study, 1655 unrelated patients with cardiovascular system diseases were simulated and analyzed based on the above background. A double luciferase reporter gene detection system verified the combination of miRNAs target recognition. The results showed that miR-485-5p significantly inhibited the luciferase activity of pGL-miR-wt but had no effect on pGL6-miR-mut. The lack of miR-485-5p can promote the activation of cardiac fibroblasts. The findings of this study can provide a new understanding and direction for the study of cardiovascular system morphology and function.

Paeonol Suppresses Vasculogenesis Through Regulating Vascular Smooth Muscle Phenotypic Switching.

OBJECTIVE: Smooth muscle cell (SMC) phenotypic switching is associated with development of a variety of occlusive vascular diseases. Paeonol has been reported to be involved in suppressing SMC proliferation. However, it is still unknown whether paeonol can regulate SMC phenotypic switching, and which eventually result in suppressing vasculogenesis. METHODS: Murine left common carotid artery was injured by completely ligation, and paeonol was administrated by intraperitoneal injection. Hematoxylin and eosin (H&E) staining was performed to visualize vascular neointima formation. Rat aortic SMCs were used to determine whether paeonol suppresses cell proliferation and migration. And murine hind limb ischemia model was performed to confirm the function role of paeonol in suppressing vasculogenesis. RESULTS: Complete ligation of murine common carotid artery successfully induced neointima formation. Paeonol treatment dramatically reduced the size of injury-induced neointima. Using rat aortic primary SMC, we identified that paeonol strongly suppressed cell proliferation, migration, and decreased extracellular matrix deposition. And paeonol treatment dramatically suppressed vasculogenesis after hind limb ischemia injury. CONCLUSION: Paeonol could regulate SMC phenotypic switching through inhibiting proliferation and migration of SMC, which results in inhibiting ischemia-induced vasculogenesis.

WWP2 and PPP1R3A are abnormally regulated in arrhythmia-induced cardiac damage.

The present work aimed to identify the roles of WWP2 (an E3 ubiquitin-protein ligase) and protein phosphatase 1 regulatory subunit 3A (PPP1R3A) in different pathological stages of cardiac arrhythmia development. Leptin-deficient mice (C57BLKS-Leprdb/Leprdb) were used for the development of initial and severe stages of cardiac arrhythmia. Histology, ECG, immunohistochemistry and Western blotting were used to analyse cardiac arrhythmia, WWP2 and PPP1R3A expression. Histopathological studies of 4-month-old mice showed cardiac degeneration, cellular lesions, and swollen tissue structure with loss of tissue elasticity, indicative of the initial condition of cardiac arrhythmia. The leptin-deficient 7-month-old mice showed cardiac tissue hardening with increased secretion of extracellular matrix. The development of initial- and severe-cardiac arrhythmia was further evident with electrocardiogram studies, which showed more PP interval variations as the disease progressed. At the molecular level, WWP2 showed marginal upregulation in the initial stages of arrhythmia and was predominantly expressed within nuclei. WWP2 was overexpressed 6.6-fold in the severe stage of cardiac arrhythmia and was spread throughout the tissue layer. Interestingly, PPP1R3A was significantly overexpressed in initial cardiac arrhythmia conditions, but was downregulated and restricted to more nuclear expression in advanced cardiac arrhythmia. Silencing of PPP1R3A, enhances the expression of WWP2 to 5.3-fold in initial stages, but remarkable variation not observed in advanced cardiac arrhythmia conditions. Our results suggest that PPP1R3A had a control over WWP2 in the initial stages of cardiac arrhythmia. In particular, PPP1R3A overexpression implies its potential protective effect in initial cardiac arrhythmia stages.