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.

Tartary buckwheat protein-derived peptide AFYRW alleviates H2O2-induced vascular injury via the PI3K/AKT/NF-κB pathway.

Tartary buckwheat protein-derived peptide (Ala-Phe-Tyr-Arg-Trp, AFYRW) is a natural active peptide that hampers the atherosclerosis process, but the underlying role of AFYRW in angiogenesis remains unknown. Here, we present a system-based study to evaluate the effects of AFYRW on H2O2-induced vascular injury in human umbilical vein endothelial cells (HUVECs). HUVECs were co-incubated with H2O2 for 2 h in the vascular injury model, and AFYRW was added 24 h in advance to investigate the protective mechanism of vascular injury. We identified that AFYRW inhibits oxidative stress, cell migration, cell invasion, and angiogenesis in H2O2-treated HUVECs. In addition, we found H2O2-induced upregulation of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), phosphorylation of nuclear factor-κB (NF-κB) p65 and nuclear translocation of NF-κB decreased by AFYRW. Taken together, AFYRW attenuated H2O2-induced vascular injury through the PI3K/AKT/NF-κB pathway. Thereby, AFYRW may serve as a therapeutic option for vascular injuries.

Microbe-Derived Butyrate and Its Receptor, Free Fatty Acid Receptor 3, But Not Free Fatty Acid Receptor 2, Mitigate Neointimal Hyperplasia Susceptibility After Arterial Injury.

Background Arterial restenosis after vascular surgery is a common cause of midterm restenosis and treatment failure. Herein, we aim to investigate the role of microbe-derived butyrate, FFAR2 (free fatty acid receptor 2), and FFAR3 (free fatty acid receptor 3) in mitigating neointimal hyperplasia development in remodeling murine arteries after injury. Methods and Results C57BL/6 mice treated with oral vancomycin before unilateral femoral wire injury to deplete gut microbiota had significantly diminished serum and stool butyrate and more neointimal hyperplasia development after arterial injury, which was reversed by concomitant butyrate supplementation. Deficiency of FFAR3 but not FFAR2, both receptors for butyrate, exacerbated neointimal hyperplasia development after injury. FFAR3 deficiency was also associated with delayed recovery of the endothelial layer in vivo. FFAR3 gene expression was observed in multiple peripheral arteries, and expression was increased after arterial injury. Treatment of endothelial but not vascular smooth muscle cells with the pharmacologic FFAR3 agonist 1-methylcyclopropane carboxylate stimulated cellular migration and proliferation in scratch assays. Conclusions Our results support a protective role for butyrate and FFAR3 in the development of neointimal hyperplasia after arterial injury and delineate activation of the butyrate-FFAR3 pathway as a valuable strategy for the prevention and treatment of neointimal hyperplasia.

Mechanism Analysis of a Novel Angiotensin-I-Converting Enzyme Inhibitory Peptide from Isochrysis zhanjiangensis Microalgae for Suppressing Vascular Injury in Human Umbilical Vein Endothelial Cells.

Microalgae are primary producers with multiple nutrients in aquatic environments and mostly have applications in biological feed and fuel industry. There are few studies assessing the angiotensin-I-converting enzyme (ACE) inhibition potential of Isochrysis zhanjiangensis, other than its antioxidant potential. In this study, we evaluated a peptide from I. zhanjiangensis (PIZ, FEIHCC) and its vascular endothelial factors and mechanism in human umbilical vein endothelial cells (HUVEC). The results reveal that PIZ (IC50 = 61.38 µM) acts against ACE in a non-competitive binding mode. In addition, PIZ inhibits angiotensin II (Ang II)-induced vascular factor secretion and expression by blocking inflammation and apoptosis through nuclear factor κB (NF-κB), nuclear erythroid 2-related factor 2 (Nrf2), mitogen-activated protein kinases (MAPKs), and the serine/threonine kinase (Akt) signal pathways. This study reveals that PIZ has potential to be developed as a therapeutic agent for hypertension and provides a new method of high-value utilization of I. zhanjiangensis.

Baicalin relieves TNF-α-evoked injury in human aortic endothelial cells by up-regulation of miR-145.

Hypertension is recognized to be associated with low-grade inflammation. Baicalin (BAI) is reported to possess various pharmacological including anti-inflammatory activities. This research explored the molecular mechanism by which BAI functions in human aortic endothelial cells (HAECs). HAECs were pretreated with BAI. Cell viability, apoptosis, and expressions of crucial proteins were respectively evaluated using cell counting kit-8 assay, flow cytometry, and western blot. Productions of cytokines were respectively assessed employing quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Cell transfection was utilized to alter miR-145 expression. The expressions of proteins participated in JNK and p38MAPK pathways were analyzed utilizing western blot. TNF-α inducement successfully evoked inflammatory injury in HAECs, exhibiting as prominently suppressed viability, while facilitated apoptosis and productions of cytokines. However, BAI pretreatment significantly ameliorated TNF-α-triggered inflammatory injuries. Besides, miR-145 expression was markedly inhibited by TNF-α inducement, while notably elevated by BAI pretreatment. Although miR-145 overexpression had no significant influence on apoptosis, miR-145 silence observably reversed BAI pretreatment-evoked protective influences on TNF-α-induced HAECs, as well as the inhibited impacts on the levels of key proteins involved in JNK and p38MAPK pathways. This investigation illustrated that BAI relieved TNF-α-triggered injuries through upregulating miR-145 via suppressing JNK and p38MAPK pathways.

Microparticle-induced vascular injury in mice following decompression is inhibited by hyperbaric oxygen: effects on microparticles and interleukin-1ß.

Hyperbaric oxygen (HBO2) became a mainstay for treating decompression sickness (DCS) because bubbles are associated with the disorder. Inflammatory processes including production of circulating microparticles (MPs) have now been shown to occur with DCS, leading to questions regarding pathophysiology and the role for HBO2. We investigated effects of HBO2 on mice exposed to 790 kPa air pressure for 2 h, which triggers elevations of MPs ladened with interleukin (IL)-1ß that cause diffuse vascular injuries. Exposure to 283 kPa O2 (HBO2) inhibited MP elevations at 2 h postdecompression by 50% when applied either prophylactically or as treatment after decompression, and the MP number remained suppressed for 13 h in the prophylactic group. Particle content of IL-1ß at 2 h postdecompression was 139.3 ± 16.2 [means ± SE; n = 11, P < 0.05) pg/million MPs vs. 8.2 ± 1.0 ( n = 15) in control mice, whereas it was 31.5 ± 6.1 ( n = 6, not significant vs. control (NS)] in mice exposed to HBO2 prophylactically, and 16.6 ± 6.3 ( n = 7, NS) when HBO2 was administered postdecompression. IL-1ß content in MPs was similar in HBO2-exposed mice at 13 h postdecompression. HBO2 also inhibited decompression-associated neutrophil activation and diffuse vascular leak. Immunoprecipitation studies demonstrated that HBO2 inhibits high-pressure-mediated neutrophil nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome oligomerization. Furthermore, MPs isolated from decompressed mice cause vascular injuries when injected into naïve mice, but if decompressed mice were exposed to HBO2 before MP harvest, vascular injuries were inhibited. We conclude that HBO2 impedes high-pressure/decompression-mediated inflammatory events by inhibiting inflammasome formation and IL-1ß production. NEW & NOTEWORTHY High pressure/decompression causes vascular damage because it stimulates production of microparticles that contain high concentrations of interleukin-1ß, and hyperbaric oxygen can prevent injuries.

Amorphous nano-selenium quantum dots improve endothelial dysfunction in rats and prevent atherosclerosis in mice through Na+/H+ exchanger 1 inhibition.

AIM: Selenium, a trace element involved in important enzymatic activities inside the body, has protective effects against cardiovascular diseases including atherosclerosis. The safe dose of selenium in the organism is very narrow, limiting the supplementation of selenium in diet. The aim of this study is to explore whether selenium quantum dots (SeQDs) prevent atherosclerosis and to investigate the potential mechanisms. METHODS: An amorphous form of SeQDs (A-SeQDs) and a crystalline form of SeQDs (C-SeQDs) were prepared through self-redox decomposition of selenosulfate precursor. Endothelial dysfunction was induced by balloon injury plus high fat diet (HFD) in rats. Atherosclerotic model was established by feeding Apoe-/- mice with HFD. RESULTS: Administrations of A-SeQDs but not C-SeQDs dramatically improved endothelium-dependent relaxation, and accelerated would healing in primary endothelial cells isolated from rats, which was comprised by co-treatment of LiCl. Lentivirus-mediated knockdown of Na+/H+ exchanger 1 (NHE1) abolished LiCl-induced endothelial dysfunction in rats. In cultured endothelial cells, A-SeQDs, as well as cariporide, inhibited NHE1 activities, decreased intracellular pH value and Ca2+ concentration, and reduced calpain activity increased by ox-LDL. These protective effects of A-SeQDs were reversed by LiCl treatment in endothelial cells. In Apoe-/- mice feeding with HFD, A-SeQDs prevented endothelial dysfunction and reduced the size of atherosclerotic plaque in aortic arteries. Further, lentivirus-mediated NHE1 gene overexpression abolished the protective effects of A-SeQDs against endothelial dysfunction and atherosclerosis in Apoe-/- mice. CONCLUSION: A-SeQDs prevents endothelial dysfunction and the growth of atherosclerotic plaque through NHE1 inhibition and subsequent inactivation of Ca2+/calpain signaling. Clinically, the administration of A-SeQDs is an effective approach to treat atherosclerosis.

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets.

Homocysteine is a sulphur-containing non-proteinogenic amino acid. Hyperhomocysteinaemia (HHcy), the pathogenic elevation of plasma homocysteine as a result of an imbalance of its metabolism, is an independent risk factor for various vascular diseases, such as atherosclerosis, hypertension, vascular calcification and aneurysm. Treatments aimed at lowering plasma homocysteine via dietary supplementation with folic acids and vitamin B are more effective in preventing vascular disease where the population has a normally low folate consumption than in areas with higher dietary folate. To date, the mechanisms of HHcy-induced vascular injury are not fully understood. HHcy increases oxidative stress and its downstream signalling pathways, resulting in vascular inflammation. HHcy also causes vascular injury via endoplasmic reticulum stress. Moreover, HHcy up-regulates pathogenic genes and down-regulates protective genes via DNA demethylation and methylation respectively. Homocysteinylation of proteins induced by homocysteine also contributes to vascular injury by modulating intracellular redox state and altering protein function. Furthermore, HHcy-induced vascular injury leads to neuronal damage and disease. Also, an HHcy-activated sympathetic system and HHcy-injured adipose tissue also cause vascular injury, thus demonstrating the interactions between the organs injured by HHcy. Here, we have summarized the recent developments in the mechanisms of HHcy-induced vascular injury, which are further considered as potential therapeutic targets in this condition. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications.

Acute vascular injury occurs in a number of important clinical contexts, including spontaneous disease-related events (e.g. plaque rupture, thrombosis) and therapeutic interventions such as angioplasty, stenting, or bypass surgery. Endothelial cell (EC) disruption exposes the underlying matrix, leading to a rapid deposition of platelets, coagulation proteins, and leukocytes. A thrombo-inflammatory response ensues characterized by leukocyte recruitment, vascular smooth muscle cell (VSMC) activation, and the elaboration of cytokines, reactive oxygen species and growth factors within the vessel wall. A resolution phase of vascular injury may be described in which leukocyte efflux, clearance of debris, and re-endothelialization occurs. VSMC migration and proliferation leads to the development of a thickened neointima that may lead to lumen compromise. Subsequent remodeling involves matrix protein deposition, and return of EC and VSMC to quiescence. Recent studies suggest that specialized pro-resolving lipid mediators (SPM) modulate key aspects of this response, and may constitute an endogenous homeostatic pathway in the vasculature. SPM exert direct effects on vascular cells that counteract inflammatory signals, reduce leukocyte adhesion, and inhibit VSMC migration and proliferation. These effects appear to be largely G-protein coupled receptor-dependent. Across a range of animal models of vascular injury, including balloon angioplasty, bypass grafting, and experimental aneurysm formation, SPM accelerate repair and reduce lesion formation. With bioactivity in the pM-nM range, a lack of discernible cytotoxicity, and a spectrum of vasculo-protective properties, SPM represent a novel class of vascular therapeutics. This review summarizes current research in this field, including a consideration of critical next steps and challenges in translation.

Treatment with high dose of atorvastatin reduces vascular injury in diabetic rats.

BACKGROUND: Previous reports showed conflicting results regarding the treatment effects of statin on Diabetes mellitus (DM). We investigated how treatment with high dose of atorvastatin affects the impaired vascular function in diabetic rats. METHODS: Atorvastatin (80mg/kg/day, oral gavage, 4 weeks) or its vehicle was administered to male control or streptozotocin (STZ)-induced diabetic rats. Aortic segments were used to investigate the vascular reactivity, protein expression of cyclooxygenase-2 (COX-2) and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) 1 (NOX1) and superoxide anions levels. RESULTS: Atorvastatin treatment did not affect glycemia levels. In diabetic rats, the vascular reactivity to phenylephrine increased compared with controls and the atorvastatin treatment reduced this response. Removal of the endothelium increased the response to phenylephrine in control rats, but not in the diabetic group. Atorvastatin increased the endothelial modulation in diabetic rats. L-NAME (100µM) increased the reactivity in all groups, but this effect was greater in atorvastatin-treated diabetic rats. Indomethacin (10µM) and NS398 (1µM) decreased the contractile response in diabetic rats and atorvastatin reversed these effects, without changing COX-2 expression. Apocynin (30µM) decreased the phenylephrine response in diabetic rats, which also showed increased NOX1 and superoxide anions; these effects were prevented by atorvastatin treatment. CONCLUSIONS: The results suggest that treatment with high dose of atorvastatin, independent of glycemia, improves endothelial function in aortas from diabetic rats by reducing the constrictor prostanoids derived from COX-2 and by reducing the oxidative stress by NADPH oxidase, as well as a possible increasing of nitric oxide participation.