Endogenous reduction of miR-185 accelerates cardiac function recovery in mice following myocardial infarction via targeting of cathepsin K.

Angiogenesis is critical for re-establishing the blood supply to the surviving myocardium after myocardial infarction (MI) in patients with acute coronary syndrome (ACS). MicroRNAs are recognised as important epigenetic regulators of endothelial function. The aim of this study was to determine the roles of microRNAs in angiogenesis. Eighteen circulating microRNAs including miR-185-5p were differently expressed in plasma from patients with ACS by high-throughput RNA sequencing. The expressional levels of miR-185-5p were dramatically reduced in hearts isolated from mice following MI and cultured human umbilical vein endothelial cells (HUVECs) under hypoxia, as determined by fluorescence in situ hybridisation and quantitative RT-PCR. Evidence from computational prediction and luciferase reporter gene activity indicated that cathepsin K (CatK) mRNA is a target of miR-185-5p. In HUVECs, miR-185-5p mimics inhibited cell proliferations, migrations and tube formations under hypoxia, while miR-185-5p inhibitors performed the opposites. Further, the inhibitory effects of miR-185-5p up-regulation on cellular functions of HUVECs were abolished by CatK gene overexpression, and adenovirus-mediated CatK gene silencing ablated these enhancive effects in HUVECs under hypoxia. In vivo studies indicated that gain-function of miR-185-5p by agomir infusion down-regulated CatK gene expression, impaired angiogenesis and delayed the recovery of cardiac functions in mice following MI. These actions of miR-185-5p agonists were mirrored by in vivo knockdown of CatK in mice with MI. Endogenous reductions of miR-185-5p in endothelial cells induced by hypoxia increase CatK gene expression to promote angiogenesis and to accelerate the recovery of cardiac function in mice following MI.

Induction of microRNA-199 by Nitric Oxide in Endothelial Cells Is Required for Nitrovasodilator Resistance via Targeting of Prostaglandin I2 Synthase.

BACKGROUND: Nitrates are widely used to treat coronary artery disease, but their therapeutic value is compromised by nitrate tolerance, because of the dysfunction of prostaglandin I2 synthase (PTGIS). MicroRNAs repress target gene expression and are recognized as important epigenetic regulators of endothelial function. The aim of this study was to determine whether nitrates induce nitrovasodilator resistance via microRNA-dependent repression of PTGIS gene expression. METHODS: Nitrovasodilator resistance was induced by nitroglycerin (100 mg·kg-1·d-1, 3 days) infusion in Apoe-/- mice. The responses of aortic arteries to nitric oxide donors were assessed in an organ chamber. The expression levels of microRNA-199 (miR-199)a/b were assayed by quantitative reverse transcription polymerase chain reaction or fluorescent in situ hybridization. RESULTS: In cultured human umbilical vein endothelial cells, nitric oxide donors induced miR-199a/b endogenous expression and downregulated PTGIS gene expression, both of which were reversed by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt or silence of serum response factor. Evidence from computational and luciferase reporter gene analyses indicates that the seed sequence of 976 to 982 in the 3'-untranslated region of PTGIS mRNA is a target of miR-199a/b. Gain functions of miR-199a/b resulting from chemical mimics or adenovirus-mediated overexpression increased PTGIS mRNA degradation in HEK293 cells and human umbilical vein endothelial cells. Furthermore, nitroglycerin-decreased PTGIS gene expression was prevented by miR-199a/b antagomirs or was mirrored by the enforced expression of miR-199a/b in human umbilical vein endothelial cells. In Apoe-/- mice, nitroglycerin induced the ectopic expression of miR-199a/b in the carotid arterial endothelium, decreased PTGIS gene expression, and instigated nitrovasodilator resistance, all of which were abrogated by miR-199a/b antagomirs or LNA-anti-miR-199. It is important that the effects of miR-199a/b inhibitions were abolished by adenovirus-mediated PTGIS deficiency. Moreover, the enforced expression of miR-199a/b in vivo repressed PTGIS gene expression and impaired the responses of aortic arteries to nitroglycerin/sodium nitroprusside/acetylcholine/cinaciguat/riociguat, whereas the exogenous expression of the PTGIS gene prevented nitrovasodilator resistance in Apoe-/- mice subjected to nitroglycerin infusion or miR-199a/b overexpression. Finally, indomethacin, iloprost, and SQ29548 improved vasorelaxation in nitroglycerin-infused Apoe-/- mice, whereas U51605 induced nitrovasodilator resistance. In humans, the increased expressions of miR-199a/b were closely associated with nitrate tolerance. CONCLUSIONS: Nitric oxide-induced ectopic expression of miR-199a/b in endothelial cells is required for nitrovasodilator resistance via the repression of PTGIS gene expression. Clinically, miR-199a/b is a novel target for the treatment of nitrate tolerance.

A minimally invasive approach to induce myocardial infarction in mice without thoracotomy.

Acute myocardial infarction (MI) is a leading cause of morbidity and mortality in the world. Traditional method to induce MI by left coronary artery (LCA) ligation is typically performed by an invasive approach that requires ventilation and thoracotomy, causing serious injuries in animals undergoing this surgery. We attempted to develop a minimally invasive method (MIM) to induce MI in mice. Under the guide of ultrasound, LCA ligation was performed in mice without ventilation and chest-opening. Compared to sham mice, MIM induced MI in mice as determined by triphenyltetrazolium chloride staining and Masson staining. Mice with MIM surgery revealed the reductions of LVEF, LVFS, E/A and ascending aorta (AAO) blood flow, and the elevations of S-T segment and serum cTn-I levels at 24 post-operative hours. The effects of MI induced by MIM were comparable to the effects of MI produced by traditional method in mice. Importantly, MIM increased the survival rates and caused less inflammation after the surgery of LCA ligation, compared to the surgery of traditional method. Further, MIM induced angiogenesis and apoptosis in ischaemic hearts from mice at postoperative 28 days as similarly as traditional method did. Finally, the MIM model was able to develop into the myocardial ischaemia/reperfusion model by using a balloon catheter with minor modifications. The MI model is able to be efficiently induced by a minimally invasive approach in mice without ventilation and chest-opening. This new model is potentially to be used in studying ischaemia-related heart diseases.

MiR-15b-5p Regulates Collateral Artery Formation by Targeting AKT3 (Protein Kinase B-3).

OBJECTIVE: To identify circulating microRNAs that are differentially expressed in severe coronary heart disease with well or poorly developed collateral arteries and to investigate their mechanisms of action in vivo and in vitro. APPROACH AND RESULTS: In our study, we identified a circulating microRNA, miR-15b-5p, with low expression that, nevertheless, characterized patients with sufficient coronary collateral artery function. Moreover, in murine hindlimb ischemia model, in situ hybridization identified that miR-15b-5p was specifically expressed in vascular endothelial cells of adductors in sham group and was remarkably downregulated after femoral artery ligation. Overexpressed miR-15b-5p significantly inhibited arteriogenesis and angiogenesis in mice. In vitro, both under basal and vascular endothelial growth factor stimulation, loss-of-function or gain-of-function studies suggested that miR-15b-5p significantly promoted or depressed the migration and proliferation of endothelial cells. We identified AKT3 (protein kinase B-3) as a direct target of miR-15b-5p. Interestingly, AKT3 deficiency by injection with Chol-AKT3-siRNA obviously suppressed arteriogenesis and the recovery of blood perfusion after femoral ligation in mice. CONCLUSIONS: These results indicate that circulating miR-15b-5p is a suitable biomarker for discriminating between patients with well-developed or poorly developed collaterals. Moreover, miR-15b-5p is a key regulator of arteriogenesis and angiogenesis, which may represent a potential therapeutic target for ischemic disease.

Role of PERK/eIF2α/CHOP Endoplasmic Reticulum Stress Pathway in Oxidized Low-density Lipoprotein Mediated Induction of Endothelial Apoptosis.

OBJECTIVE: PERK/eIF2α/CHOP is a major signaling pathway mediating endoplasmic reticulum (ER) stress related with atherosclerosis. Oxidized LDL (ox-LDL) also induces endothelial apoptosis and plays a vital role in the initiation and progression of atherosclerosis. The present study was conducted to explore the regulatory effect of ox-LDL on PERK/eIF2α/CHOP signaling pathway in vascular endothelial cells. METHODS: The effects of ox-LDL on PERK and p-eIF2α protein expression of primary human umbilical vein endothelial cells (HUVECs) were investigated by Western blot analysis. PERK gene silencing and selective eIF2α phosphatase inhibitor, salubrinal were used to inhibit the process of ox-LDL induced endothelial cell apoptosis, caspase-3 activity, and CHOP mRNA level. RESULTS: Ox-LDL treatment significantly increased the expression of PERK, PERK-mediated inactivation of eIF2α phosphorylation, and the expression of CHOP, as well as the caspase-3 activity and apoptosis. The effects of ox-LDL were markedly decreased by knocking down PERK with stable transduction of lentiviral shRNA or by selective eIF2α phosphatase inhibitor, salubrinal. CONCLUSION: This study provides the first evidence that ox-LDL induces apoptosis in vascular endothelial cells mediated largely via the PERK/eIF2α/CHOP ER-stress pathway. It adds new insights into the molecular mechanisms underlying the pathogenesis and progression of atherosclerosis.

Accelerated onset of senescence of endothelial progenitor cells in patients with type 2 diabetes mellitus: role of dimethylarginine dimethylaminohydrolase 2 and asymmetric dimethylarginine.

The risk of cardiovascular complications in diabetic patients is mainly associated with endothelial dysfunction. Reduced number of EPCs and impaired function of EPCs in diabetes result in imbalance of endothelial homeostasis and dysfunction of vessels. In patients with diabetes mellitus, plasma levels of asymmetric dimethylarginine (ADMA) were elevated, while the expression and activity of dimethylarginine dimethylaminohydrolase (DDAH) were reduced. In the present study, we investigated the role of the DDAH2/ADMA pathway in the senescence of EPCs in type 2 diabetic patients and cultured EPCs treated with high glucose. The results showed that the percentage of senescent EPCs increased while the expression of DDAH2 decreased concomitantly with an increase in the plasma levels of ADMA in patients with type 2 diabetes mellitus (T2DM). Similar results were seen in cultured EPCs treated with high glucose. Exogenous application of ADMA accelerated the senescence of EPCs in a dose-dependent manner, and overexpression of DDAH2 inhibited high glucose-induced EPCs senescence. In addition, it has also been reported that DDAH/ADMA pathway is regulated by silent information regulator 1 (SIRT1) in endothelial cell. In the present study, we found decreased expression of SIRT1 both in T2DM patients and EPCs pretreated with high glucose. And resveratrol (activating SIRT1) inhibited high glucose-induced EPCs senescence by upregulating the expression of DDAH2 and decreasing the levels of ADMA. Taken together, we concluded that DDAH2/ADMA is involved in the accelerated senescence of EPCs in diabetes, which is associated with the activation of SIRT1.

Asymmetric dimethylarginine triggers macrophage apoptosis via the endoplasmic reticulum stress pathway.

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is emerging as a key contributing factor in atherogenesis, a process in turn known to involve macrophage apoptosis. The aim of this study was to determine the effect of ADMA on macrophage apoptosis, with specific reference to the endoplasmic reticulum (ER) stress pathway. Macrophage apoptosis was evaluated by Annexin V- Propidium iodide (PI) and Hoechst 33258 staining assays. Levels of the ER stress marker glucose regulated protein 78 (GRP78) were characterized by western blot. Levels of the proapoptotic C/EBP-homologous protein (CHOP) were evaluated by western blot and reverse transcription polymerase chain reaction (RT-PCR), and caspase-4 activity was measured using a colorimetric protease assay kit. We observed ADMA dose- and time-dependent increases in macrophage levels of GRP78. Similar ADMA dose- and time-dependent increases were detected in intracellular caspase-4 activity and macrophage apoptosis, all of which were sensitive to treatment with siRNAs for protein kinase RNA-like ER kinase and inositol-requiring protein-1 (IRE1), the ADMA antagonist L-arginine, as well as inhibitors of eukaryotic translation initiation factor-2 (salubrinal), IRE1 (irestatin 9389), and c-Jun N-terminal kinase (SP600125). Our results indicate that ADMA triggers macrophage apoptosis via the ER stress pathway.

Regulation of endothelial progenitor cell differentiation and function by dimethylarginine dimethylaminohydrolase 2 in an asymmetric dimethylarginine-independent manner.

Endothelial progenitor cells (EPCs) are involved in the repair of vessels and angiogenesis and are useful in the treatment of ischemic diseases. The dimethylarginine dimethylaminohydrolase (DDAH)/asymmetric dimethylarginine (ADMA) pathway is regulated by silent information regulator 1 (SIRT1), leading to the senescence of endothelial cells (ECs). Here, we demonstrated that peripheral blood EPCs predominantly expressed DDAH2 that increased with EPC differentiation. EPC senescence and dysfunction were induced on interruption of DDAH2 expression, whereas the mRNA expression of vascular endothelial growth factor (VEGF) and kinase-domain insert containing receptor (KDR) were downregulated. Moreover, SIRT1 expression increased with EPC differentiation. Interruption of SIRT1 inhibited DDAH2, VEGF, and KDR expression, but had no effect on the level of ADMA. From our data, we concluded that DDAH2 is involved in the differentiation of EPCs and regulates the senescence and function of EPCs through the VEGF/KDR pathway by activation of SIRT1.

Inhibitory effect of reinioside C on vascular smooth muscle cells proliferation induced by angiotensin II via inhibiting NADPH oxidase-ROS-ENK1/2-NF-kappaB-AP-1 pathway.

The proliferation of vascular smooth muscle cells (VSMCs) induced by angiotensin II (Ang II) plays a vital role in the pathogenesis of arteriosclerosis and restenosis. In the present study, the effect of reinioside C, a main active ingredient of Polygala fallax Hemsl, on proliferation of VSMCs induced by Ang II was investigated. It was found that Ang II (1 microM) markedly stimulated proliferation of VSMCs. Pretreatment of reinioside C (3, 10 or 30 microM) concentration-dependently inhibited the proliferative effect of Ang II. To determine the possible mechanism, NADPH oxidase subunits (Nox-1, Nox-4) mRNA expression, intracellular ROS level, phosphorylation of ERK1/2, NF-kappaB activity, and mRNA expression of AP-1 subunits (c-fos, c-jun) and c-myc were measured. The results demonstrated that reinioside C attenuated Ang II-induced NADPH oxidase mRNA expression, generation of ROS, ERK1/2 phosphorylation, activation of NF-kappaB, and mRNA expression of AP-1 and c-myc in VSMCs in a concentration-dependent manner. The effects of Ang II were also inhibited by diphenyleneiodonium (DPI, the NADPH oxidase inhibitor), PD98059 (the ERK1/2 inhibitor) and pyrrolidine dithiocarbamate (PDTC, the NF-kappaB inhibitor). These results suggest reinioside C attenuates Ang II-induced proliferation of VSMCs by inhibiting NADPH oxidase-ROS-ERK1/2-NF-kappaB-AP-1 pathway.

Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1.

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF.

Ang II induces capillary formation from endothelial cells via the AT1R-dependent inositol requiring enzyme 1 pathway.

Previous studies have demonstrated an important interaction between angiotension II type 1 receptor (AT1R) and angiotension II (Ang II) -induced capillary formation from endothelial cells and vascular endothelial growth factor (VEGF). However, the underlying mechanism remains elusive. Recent studies revealed that the unfolded protein response regulates an angiogenic response by the kidney epithelium during ischemic stress. Therefore, in the present study, we investigated the effects of Ang II on AT1R-mediated capillary formation from endothelial cells and the possible involvement of the IRE1/JNK/p38 MAPK pathway. Our results show that Ang II (1 nmol/L) induced the expression of VEGF and enhanced capillary formation from endothelial cells in the Matrigel assay. This effect was significantly depressed by the AT1R blocker losartan and different inhibitors (irestatin, IRE1 specific inhibitor; SP600125, JNK specific inhibitor; SB203580, p38 MAPK specific inhibitor) but not by the AT2R blocker PD123319. Next, we investigated the effect of Ang II on the IRE1/JNK/p38 MAPK pathway and the 78kDA glucose regulated protein 78 (GRP78) activity in HUVECs and the role of the AT1 Receptor. The results show that Ang II activated both the IRE1/JNK/p38 MAPK pathway and GRP78 binding activity. These effects were markedly inhibited by the AT1R blocker losartan. The IRE1 specific inhibitor irestatin, the JNK specific inhibitor SP600125, and the p38 MAPK specific inhibitor SB203580 significantly inhibited Ang II-induced capillary formation from endothelial cells and VEGF expression but had no effect on GRP78. Collectively, these findings suggest for the first time that Ang II promotes capillary formation by inducing the expression of VEGF via Ang II type 1 receptor-mediated stimulation of the IRE1/JNK/p38 MAPK pathway.

Targeted introduction of tissue plasminogen activator (TPA) at the AAVS1 locus in mesenchymal stem cells (MSCs) and its stable and effective expression.

Thrombolytic therapy using tissue plasminogen activator (TPA) is an effective method for treating acute myocardial infarction. However, the systemic administration of TPA is associated with the risk of hemorrhage. Mesenchymal stem cells (MSCs) from bone marrow are characterized by low immunogenicity and homing toward damaged tissues and are therefore ideal cell carriers to achieve lesion-targeting medication. In this article, TPA gene was integrated into the AAVS1 of mesenchymal stem cells, which has been confirmed to be a safe chromosomal locus. The targeting efficiency was 83%. The clones with the site-specific integration retained the stem cell traits of MSCs, displayed a normal karyotype and could persistently and effectively express TPA, as demonstrated by an average expression activity of 1.5 units/mL (3.4-fold that of the control group). After subculture and subsequent growth for two weeks, the clones showed an average TPA activity of 1.43 units/mL and exhibited no significant differences among the individual clones. In summary, the foreign TPA gene can be specifically introduced to the AAVS1 locus, whereby it can be stably and effectively expressed. MSCs can serve as cell carriers for the targeted treatment of a thrombus using TPA.

Endothelial GLUTs and vascular biology.

Endothelial metabolism is a promising target for vascular functional regulation and disease therapy. Glucose is the primary fuel for endothelial metabolism, supporting ATP generation and endothelial cell survival. Multiple studies have discussed the role of endothelial glucose catabolism, such as glycolysis and oxidative phosphorylation, in vascular functional remodeling. However, the role of the first gatekeepers of endothelial glucose utilization, glucose transporters, in the vasculature has long been neglected. Here, this review summarizes glucose transporter studies in vascular research. We mainly focus on GLUT1 and GLUT3 because they are the most critical glucose transporters responsible for most endothelial glucose uptake. Some interesting topics are also discussed, intending to provide directions for endothelial glucose transporter research in the future.

[Thermal Environment Evolution and Response Mechanism of Urban Sprawl Based on Multi-source Data].

Improving the urban thermal environment and improving the quality of human settlements are important prerequisites for creating ecologically livable cities. The current research on the relationship between urban expansion and the thermal environment is mostly based on remote sensing data, and the application of multi-source data is weak. Here, we selected the Xi'an metropolitan core area, measured the urban expansion and temporal and spatial evolution of the thermal environment based on Landsat remote sensing images in 2010 and 2020, and used multi-source data, such as interest points and the Baidu thermal index, to study the response mechanism of the urban thermal environment through geoscience statistical analysis methods. The results showed that:① the construction land in the study area had expanded by 200.84 km2, and the area and intensity showed that "the center and the periphery are weaker, and the difference between the two" characteristics, and the expansion mode was mainly edge type and infill type. ② Between 2010 and 2020, the overall thermal environment in the study area deteriorated, and the area of the heat island area increased by 282.65 km2. The spread of the heat island area was in the same direction as the urban expansion, and the distribution pattern evolved from "southeast-northwest" to "northeast-southwest;" however, the average temperature in the central area of the city decreased 1.09℃. ③ Urban expansion was strongly positively correlated with the deterioration of the urban thermal environment. The expansion of urban space had a contribution rate of 60.40% to the deterioration of the thermal environment, and various socio-economic factors had a weaker effect, with an overall contribution rate of 39.60%. The vegetation water body had an obvious cooling effect; under the influence of multiple factors, the surface temperature increased by 0.241 units. In the process of urban expansion, changes in surface parameters and two-dimensional urban morphology were still the main factors for thermal environment changes, whereas three-dimensional morphology had a small effect on the warming of social and economic activities, and the contribution of water bodies and vegetation to cooling was prominent.

Nitrosative stress induced by homocysteine thiolactone drives vascular cognitive impairments via GTP cyclohydrolase 1 S-nitrosylation in vivo.

BACKGROUND: s: Hyperhomocysteinemia (HHcy) is one of risk factors for vascular cognitive impairment (VCI). GTP cyclohydrolase 1 (GCH1) deficiency is critical to oxidative stress in vascular dysfunction. The aim of this study was designed to examine whether HHcy induces VCI through GCH1 S-nitrosylation, a redox-related post-translational modification of cysteine. METHODS: The VCI model was induced by feeding mice homocysteine thiolactone (HTL) for 16 consecutive weeks. The cognitive functions were evaluated by step-down avoidance test, passive avoidance step-through task test, and Morris water maze (MWM) test. Protein S-nitrosylation was assayed using a biotin-switch method. RESULTS: In cell-free system, nitric oxide (NO) donor induced GCH1 protein S-nitrosylation and decreased GCH1 activity. In endothelial cells, HTL increased GCH1 S-nitrosylation, reduced tetrahydrobiopterin, and induced oxidative stress, which were attenuated by N-acetyl-cysteine, L-N6-1-Iminoethyl-lysine, mutant of GCH1 cysteine 141 to alanine (MT-GCH1) or gene deletion of inducible NO synthase (iNOS). Further, HTL incubation or iNOS overexpression promoted endothelial cellular senescence, but abolished by exogenous expression of MT-GCH1 or pharmacological approaches including N-acetyl-cysteine, L-sepiapterin, and tempol. In wildtype mice, long-term administration of HTL induced GCH1 S-nitrosylation and vascular stiffness, decreased cerebral blood flow, and damaged the cognitive functions. However, these abnormalities induced by HTL administration were rescued by enforced expression of MT-GCH1 or gene knockout of iNOS. In human subjects, GCH1 S-nitrosylation was increased and cognitive functions were impaired in patients with HHcy. CONCLUSION: The iNOS-mediated nitrosative stress induced by HTL drives GCH1 S-nitrosylation to induce cerebral vascular stiffness and cognitive impairments.

The hydromechanics in arteriogenesis.

Coronary heart diseases are tightly associated with aging. Although current revascularization therapies, such as percutaneous coronary interventions (PCI) and coronary artery bypass graft (CABG), improve the clinical outcomes of patients with coronary diseases, their application and therapeutic effects are limited in elderly patients. Thus, developing novel therapeutic strategies, like prompting collateral development or the process of arteriogenesis, is necessary for the treatment of the elderly with coronary diseases. Arteriogenesis (ie, the vascular remodeling from pre-existent arterioles to collateral conductance networks) functions as an essential compensation for tissue hypoperfusion caused by artery occlusion or stenosis, and its mechanisms remain to be elucidated. In this review, we will summarize the roles of the major hydromechanical components in laminar conditions in arteriogenesis, and discuss the potential effects of disturbed flow components in non-laminar conditions.

[Characteristics and driving forces of wetland landscape pattern evolution of the city belt along the Yellow River in Ningxia, China]. / å®å¤æ²¿é»„åŸŽå¸‚å¸¦æ¹¿åœ°æ™¯è§‚æ ¼å±€æ¼”å˜ç‰¹å¾åŠé©±åŠ¨åŠ›.

Wetlands are one of the most productive ecosystems in the world, with functions of water purification, climate regulation, and carbon sinks. Due to the stresses caused by human social development and changes of natural conditions, wetlands have been seriously damaged. We examined the evolutionary law of landscape pattern of wetland along the Yellow River, and acquainted the current situation of wetland resources and dynamic change. Based on satellite images of year 2000, 2009, and 2018 from Landsat, we used landscape indices and geographic detectors to quantitatively analyze the characteristics and driving forces of wetland landscape pattern evolution of the city belt along the Yellow River in Ningxia from 2000 to 2018. The results showed that the wetland area of the city belt along the Yellow River in Ningxia enlarged first and then decreased from 2000 to 2018. The wetland area increased by 52.2 km2 in the early stage of the study with an increasing rate of 8.2%, and decreased by 26.8 km2 with a reduction rate of 3.9% in the later stage. The wetland was mainly transformed to construction land and unused land, with transfer out area being 166.7 and 158.4 km2 respectively. New wetland was mainly transformed from unused land, forest, and grassland, with an area of 543.1 km2. The fragmentation degree of wetland landscape in city belt was increasing, the balanced distribution of all kinds of wetlands was gradually strengthened, the landscape diversity was increasing, and the dominant landscape types were gradually weakening. Natural factors and socio-economic factors jointly affected the evolution of wetland landscape pattern in city belt. Among all socio-economic factors population was the most important one. Among natural factors, precipitation and temperature were important. Other driving factors were relatively weak, but could not be ignored.

The dynamics of monocytes in the process of collateralization.

Collateralization is an important way for patients with coronary heart disease to supply blood flow to the ischemic area. At present, research on the mechanism of collateral circulation mainly focuses on the inflammatory response. Monocytes are the kernel of inflammatory response during arteriogenesis. Therefore, we reviewed the recent developments in this field in terms of the dynamic changes of monocytes during collateralization. We searched and scanned PubMed for the following terms until November 2018: collateral, collateralization, monocyte, macrophage, and arteriogenesis. Articles were obtained and examined to figure out the dynamics of monocytes in the progress of collateralization. Substantial research shows that recruitment, infiltration, and phenotypic transformation of monocytes can affect function in various ways, respectively. Mechanical or chemical factors that can produce effects on collateral development may be due partly to impact on dynamics of monocytes. Although mechanisms of dynamics of monocytes during arteriogenesis are not elucidated clearly, there is no doubt that deeper exploration of the underlying mechanisms will contribute to pharmaceutical development aiming for promoting collateral development.

[Spatial differentiation characteristics and influencing factors of urban and rural settlements in Tibet, China]. / è¥¿è—åŸŽä¹¡å± æ°‘ç‚¹ç©ºé—´åˆ†å¼‚ç‰¹å¾ä¸Žå½±å“å› ç´ .

Located in the hinterland of the Qinghai-Tibet Plateau, Tibet has very limited space sui-table for human living. The spatial distribution of settlements in Tibet is restricted by multiple factors. To reveal the spatial distribution characteristics and explore the main influencing factors of settlements in Tibet, we extracted patch data from the high-resolution images of urban and rural settlements in Tibet based on visual interpretation. Methods such as the kernel density analysis, space hotspot detection, Geodetector and others were applied to analyze the spatial differentiation characteristics and influencing factors, with the aim to provide reference for future settlements selection and formulation of relevant policies on regional economic development in the plateau region. The results showed that urban and rural settlements in Tibet had a clustering pattern, with different overall density distribution. Lhasa was a high-density core, and Ngari Prefecture, Qamdo, and Nyingchi were the "core-edge" structures with low-density edges. The settlement density of Lhasa was as high as 220 ind·km-2, while that of Ngari Prefecture, Qamdo and Nyingchi was only 5.7 ind·km-2. The gap between the two regions was more than 43 times. The clustering of high and low value clusters in urban and rural settlements was remarkable. The number of high-value of large plaques was rare, and the number of low-values of small plaques was dominant. The area of high-value cluster accounted for only 3.7%, concentrated in Lhasa and Lhoka. The proportion of low value cluster area reached 67.2%, mainly distributed in Ngari Prefecture and Nagqu on the Qiangtang Plateau. There were six types of urban and rural settlements in Tibet, which formed two circle structures in the "One River and Two Streams" basin and the "Three Rivers" basin. From the inside to the outside, the large plaque-dominated type, medium-density and cluster-like type, high-density and point-scattered type, low-density and point-scattered type and high-altitude and uninhabited type was successively distributed. Lhasa was dominated by medium-density and cluster-like type, accounting for 31%. Lhoka was dominated by low-density and point-scattered type, accounting for 38%. Qamdo was mainly low-density and point-scattered type, accounting for 51%. The Ngari Prefecture, Nagqu and Shigatse were dominated by high-altitude and uninhabited type, and the proportion of the Ngari Prefecture was as high as 64%. The effects of different factors on the spatial distribution of urban and rural settlements in Tibet were distinctly different. The population and GDP were highly decisive for the distribution of urban and rural settlements. In addition, urban settlements showed strong road orientation, while rural settlements were more characterized by river orientation.

S-Nitrosylation of Prostacyclin Synthase Instigates Nitrate Cross-Tolerance In Vivo.

Development of nitrate tolerance is a major drawback to nitrate therapy. Prostacyclin (PGI2) is a powerful vasodilator produced from prostaglandin (PGH2) by prostacyclin synthase (PGIS) in endothelial cells. This study aimed to determine the role of PGIS S-nitrosylation in nitrate tolerance induced by nitroglycerin (GTN). In endothelial cells, GTN increased PGIS S-nitrosylation and disturbed PGH2 metabolism, which were normalized by mutants of PGIS cysteine 231/441 to alanine (C231/441A). Clearance of nitric oxide by carboxy-PTIO or inhibition of S-nitrosylation by N-acetyl-cysteine decreased GTN-induced PGIS S-nitrosylation. Enforced expression of mutated PGIS with C231/441A markedly abolished GTN-induced PGIS S-nitrosylation and nitrate cross-tolerance in Apoe-/- mice. Inhibition of cyclooxygenase 1 by aspirin, supplementation of PGI2 by beraprost, and inhibition of PGIS S-nitrosylation by N-acetyl-cysteine improved GTN-induced nitrate cross-tolerance in rats. In patients, increased PGIS S-nitrosylation was associated with nitrate tolerance. In conclusion, GTN induces nitrate cross-tolerance through PGIS S-nitrosylation at cysteine 231/441.