Aryl hydrocarbon receptor connects dysregulated immune cells to atherosclerosis.

As a chronic inflammatory disease with autoimmune components, atherosclerosis is the major cause of cardiovascular morbidity and mortality. Recent studies have revealed that the development of atherosclerosis is strongly linked to the functional activities of aryl hydrocarbon receptor (AHR), a chemical sensor that is also important for the development, maintenance, and function of a variety of immune cells. In this review, we focus on the impact of AHR signaling on the different cell types that are closely related to the atherogenesis, including T cells, B cells, dendritic cells, macrophages, foam cells, and hematopoietic stem cells in the arterial walls, and summarize the latest development on the interplay between this environmental sensor and immune cells in the context of atherosclerosis. Hopefully, elucidation of the role of AHR in atherosclerosis will facilitate the understanding of case variation in disease prevalence and may aid in the development of novel therapies.

miR-155 induces endothelial cell apoptosis and inflammatory response in atherosclerosis by regulating Bmal1.

Atherosclerosis is the leading cause of death from vascular diseases worldwide, and endothelial cell (EC) dysfunction is the key cause of atherosclerosis. miR-155 was found to induce endothelial injury and to trigger atherosclerosis. In addition, brain and muscle ARNT-like protein-1 (Bmal1) has been found to be closely related to EC function. Therefore, the present study aimed to explore the mechanism underlying the regulation of Bmal1 by miR-155 in the induction of EC apoptosis and inflammatory response in atherosclerosis. The atherosclerosis model in apolipoprotein E (ApoE)- / - mice was established. miR-155 and Bmal1 expression was quantified by RT-qPCR and western blot analysis, respectively. The role of miR-155 and Bmal1 in atherosclerosis was evaluated through changes in cardiac function, plaque area, cardiomyocyte apoptosis, and inflammatory factor levels in mice. Moreover, the regulatory relationship between them was identified by dual-luciferase reporter gene assay to explore the mechanism of action of miR-155. After the modeling, the expression of miR-155 was upregulated and Bmal1 was downregulated in aorta, and there was a significant linear correlation between them. Upregulation of miR-155 increased the atherosclerotic plaque area, cell apoptosis, total cholesterol (TC) and triglyceride (TG), as well as weakened aortic diastolic function. However, opposite changes occurred after downregulation of miR-155 or an increase in Bmal1. In addition, the microRNA.org website predicted that there were targeted binding sites between miR-155 and Bmal1, which was verified with a dual-luciferase reporter gene assay. miR-155 was able to inhibit the expression by targeting Bmal1. Moreover, a rescue experiment showed that Bmal1 hindered the promotion of miR-155 in regards to atherosclerosis. In conclusion, miR-155 induces EC apoptosis and inflammatory response, weakens aortic diastolic function, and promotes the progression of atherosclerosis through targeted inhibition of Bmal1.

LncRNA SNHG1 alleviates hypoxia-reoxygenation-induced vascular endothelial cell injury as a competing endogenous RNA through the HIF-1α/VEGF signal pathway.

Long noncoding ribonucleic acids (lncRNAs) are critical regulators in various biological processes. In the present study, we aimed to explore whether miR140-3p was involved in the underlying molecular mechanisms of small nucleolar RNA host gene 1 (SNHG1) in myocardial ischemia/reperfusion (I/R) injury. A mouse model of I/R injury and hypoxia-reoxygenation (H/R)-stimulated human umbilical vein endothelial cells (HUVECs) was used in this study. Cell proliferation was detected by MTT. The mRNA and protein levels of vascular endothelial growth factor (VEGF), VE-cadherin, and MMP2 were detected by RT-PCR and western blot, respectively. The angiogenesis was assessed by tube formation assay. Cell migration was assessed using wound-healing assay. Results showed that SNHG1 expression was increased in the cardiac microvasculature of a mouse model of I/R injury and in H/R-stimulated HUVECs. H/R stimulation significantly reduced cell proliferation, tube formation, and cell migration, but increased expression of VEGF, VE-cadherin, and MMP2. SNHG1 upregulation under H/R increased HUVECs proliferation, tube formation, and cell migration, and upregulated expression of VEGF, VE-cadherin, and MMP2, compared with the H/R group. SNHG1 knockdown exhibited the opposite effect. SNHG1 functioned as a competing endogenous RNA (ceRNA) of miR-140-3p. HIF-1α was identified as a target of miR-140-3p. SNHG1 upregulation enhanced cell proliferation, tube formation, and expression of VEGF, VE-cadherin, and MMP2 through HIF-1α/VEGF signaling. This process could be offset by miR-140-3p mimic or VEGF inhibitor. Our results reveal a novel protective function of SNHG1 that furthers understanding of cardiac I/R injury and provides experimental evidence for future therapy.

Cystatin C regulates major histocompatibility complex-II-peptide presentation and extracellular signal-regulated kinase-dependent polarizing cytokine production by bone marrow-derived dendritic cells.

Cystatin C is a ubiquitously expressed cysteine protease inhibitor that protects cells from either improper hydrolysis by endogenous proteases or pathogen growth/virulence by exogenous proteases. Although commonly used as a serum biomarker for evaluating renal function, cystatin C is associated with many immunological disorders under various pathophysiological conditions. How cystatin C affects immune cells, especially dendritic cells (DCs), however, is far from clear. In this study, we found that pharmacological treatment with or genetic overexpression of cystatin C in bone marrow-derived DCs (BMDCs) reduced their capacity to stimulate CD4+ T-cell proliferation, despite increased antigen uptake. This reduced capacity corresponded with reduced major histocompatibility complex-II presentation owing to diminished levels of the chaperon H2-DM in BMDCs. Instead of promoting proliferation, cystatin C promoted skewing of T cells toward proinflammatory T-helper (Th)1/Th17 differentiation. This was mediated by augmented extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase phosphorylation in BMDCs, leading to secretion of polarizing cytokines, which in turn led to the Th deviation. Collectively, our study explained the cellular and molecular basis of how this protease inhibitor can regulate immune responses, namely by affecting BMDCs and their cytokine pathway. Our results might open up an avenue for the development of therapeutic agents for the treatment of cystatin C-related immunological diseases.

[Anatomy and clinical application of bypass circuit outflow tract of arterial sclerosis obstruction].

OBJECTIVE: To evaluate the possibility of collateral outflow tract of arterial sclerosis obstruction (ASO) and the prospect of clinical application. METHODS: The red emulsion was infused into the arteries of the above knee amputation of 10 fresh specimens. Then the pathological changes of the anterior tibial artery, posterior tibial artery and the popliteal artery, and the contribution of these bole artery branch were observed. From September 2005 to April 2007, 5 patients with ASO were treated, unilateral lower limb was involved in all cases. There were 3 males and 2 females, aged 68-81 years. The arteriography and Color Doppler ultrasound of lower limbs showed that the femoral artery and the popliteal artery and the branches had no development. The exploratory operation on the popliteal artery and the branches was carried out. RESULTS: The walls of the anterior tibial artery, posterior tibial artery, and the popliteal artery were stiff and the lumens were filled with atheromatous plaque. The sural arteries opening to the bole artery was frequent. The collateral circulation at the knee perimeter was raritan rather affluent at the muscle group. All of the operations were successful, the skin temperature increased gradually after operation, and the degrees of blood oxygen saturation increased to 90%-100% at 6 hours from 0 before operation. After a follow-up of 3 to 12 months, the symptom improved obviously, rest pain disappeared, lower limb ulcer healed. The Color Doppler ultrasound showed that most of the blood flow at the anastomotic stoma ejected into bypass circuit, and the blood flow at the distally posterior tibial artery and anterior tibial artery was little. CONCLUSION: The collateral outflow tract construction is feasible, it is an effective path after clinical verification to solve the advanced stage ASO.