Vascular-related Diseases Research Articles

Numerical investigation of flow parameters for solid rigid spheroidal particle in a pulsatile pipe flow

Quantifying, forecasting and analysing the displacement rates of suspended particles are essential while discussing about blood flow analysis. Because blood is one of the major organs in the body, which enables transport phenomena, comprising of numerous blood cells. In order to model the blood flow, a flow domain was created and numerically simulated. Flow field velocity in the stream is solved utilizing Finite Volume Method utilizing FVM unstructured solver. In pulsatile flow, the effect of parameters such as average Reynolds number, tube radius, particle size and Womersley number are taken into account. In this study spheroidal particle trajectory in axial direction is simulated at different values of pulsating frequency including 1.2 Hz, 3.33 Hz and 4.00 Hz and various densities including 1005 kg/m3 and 1025 kg/m3 for the flow domain. The analysis accomplishes the interaction study of blood constituents for different flow situations which have applications in diagnosis and treatment of cardio vascular related diseases.

094 HOSPITAL ACQUIRED ACUTE KIDNEY INJURY INCIDENCE AND ITS OUTCOME IN GERIATRIC PATIENTS ADMITTED TO HOSPITAL KAJANG

Category: Epidemiology and Outcomes from AKI Presenter: Dr LAILATULEMA ABBAS Keywords: hospital acquired acute kidney injury, incidence Acute kidney injury in hospitalized patients is associated with significant morbidity and mortality. The spectrum of hospital acquired acute kidney injury (HA-AKI) ranges from asymptomatic to a completely anuric state. Advanced age group postulated to be a probable risk factor for AKI during hospitalization. To study the HA-AKI incidence and outcome of HA-AKI in geriatric patients admitted to a district hospital. An observational study of HA-AKI patients admitted to general medical wards from 1stNovember 2016 to 31st December 2016 was conducted. All geriatric patients aged more than 65 years old were included. According to Kidney Disease: Improving Global Outline (KDIGO), HA-AKI was defined as raised in serum creatinine of more than 26μmol/L 48 hours after hospitalization. Medical records were reviewed retrospectively. Incidence: There were 1319 admissions during the study period. Six patients excluded from the dataset due to missing medical records. Only 45 HA-AKI cases were included. The incidence of HAAKI were 3.4% (n= 45). Patients were 25 (55.6%) male, and 20 (44.4%) female. The mean age was 58.7 ± 16.9 years, whereas average length of stay was 9.1 ± 6.8 days. The commonest cause of HA-AKI observed were sepsis 21 (46.7%) cases, acute coronary syndrome 6 (13.3%) cases and vascular-related disease 6 (13.3%) cases. While most patients had diabetes, only 3 (6.6%) patients had background of chronic kidney disease (CKD). Geriatric Outcome: There were 20 (44.4%) geriatric patients identified. Two (18.2%) patients had complete recovery of renal function while 9 (81.8%) patients progressed to CKD. However, 9 (45%) patients succumbed to the illness during admission. Only 1 (5%) patient had renal replacement therapy done during the course of hospitalization. Geriatric patients with HA-AKI has risk of developing CKD upon discharge therefore prevention and management strategies for this condition need to be identified to limit the risks of susceptible patients.

Descriptive study of relationship between cardio-ankle vascular index and biomarkers in vascular-related diseases

ABSTRACTBackground: Cardio-ankle vascular index (CAVI) was supposed to be an independent predictor for vascular-related events. Biomarkers such as homocysteine (Hcy), N-terminal pro-brain natriuretic peptide (NT-proBNP), and urine albumin(microalbumin) (UAE) have involved the pathophysiological development of arteriosclerosis. The present study was to investigate relationship between CAVI and biomarkers in vascular-related diseases. Methods: A total of 656 subjects (M/F 272/384) from department of Vascular Medicine were enrolled into our study. They were divided into four groups according to the numbers of suffered diseases, healthy group (group 0: subjects without diseases of hypertension, diabetes mellitus (DM), coronary heart disease (CHD); n = 186), group 1 (with one of diseases of hypertension, CHD, DM; n = 237), group 2 (with two of diseases of hypertension, CHD, DM; n = 174), and group 3 (with all diseases of hypertension, CHD, DM; n = 59). CAVI was measured by VS-1000 apparatus. Results: CAVI was increasing with increasing numbers of suffered vascular-related diseases. Similar results were found in the parameters of biomarkers such as Hcy, log NT-ProBNP, and log UAE. There were positive correlation between log NT-proBNP, Hcy, log UAE, and CAVI in the entire study group and nonhealthy group. Positive correlation between log UAE and CAVI were found in the entire study group after adjusting for age, body mass index (BMI), blood pressure, uric acid, and lipids. Multivariate analysis showed that log UAE was an independent associating factor of CAVI in all subjects. Conclusions: CAVI was significantly higher in subjects with hypertension, CHD, and DM. There was correlation between arterial stiffness and biomarkers such as NT-proBNP, Hcy, and UAE.

Crocetin restores diabetic endothelial progenitor cell dysfunction by enhancing NO bioavailability via regulation of PI3K/AKT-eNOS and ROS pathways

AimsEndothelial progenitor cell (EPC) dysfunction underlies a critical risk factor in diabetic vascular complications due to function defect in restoring endothelium injury. Crocetin has attracted increasing attention in several vascular-related diseases. In present study, we aimed to explore the role of crocetin in diabetic EPC dysfunction. Main methodsEPCs were isolated from bone marrow in diabetic mice and identified using the fluorescence staining and flow cytometry. After exposure to various doses of crocetin, cell viability was detected by MTT assy. Then, colony formation, lactate dehydrogenase (LDH) release, cell apoptosis and caspase-3 activity were assessed. The underlying mechanism was also investigated by western blotting. Key findingsEPCs from diabetic mice exhibited dysfunction under hyperglycemia condition. Interestingly, crocetin treatment alleviated the impairment in diabetic EPC proliferation and colony formation. Simultaneously, the increases in LDH release, cell apoptosis and caspase-3 activity were also restrained following crocetin stimulation. Additionally, EPC migration response to SDF-1 was also impaired under diabetic condition, which was partly restored by crocetin. Mechanism analysis manifested that administration with crocetin repaired the damage in the activation of PI3K/AKT-eNOS pathway and NO production, but attenuated ROS elevation in diabetic EPCs. Importantly, preconditioning with antagonist of LY294002 (for PI3K/AKT) or NG-monomethyl-l-arginine (for eNOS) antagonized the beneficial effect of crocetin on diabetic EPC dysfunction. SignificanceThese data corroborated that crocetin could restore the dysfunction of diabetic EPCs by enhancing NO bioavailability via regulation of PI3K/AKT-eNOS and ROS pathways. Therefore, this research supports a potential promising therapeutic aspect for diabetic patients.

The design and rationale of the Beijing Vascular Disease Patients Evaluation Study (BEST study).

AimsArteriosclerosis and arterial stiffness increasing are the basic pathophysiological changes of vascular-related diseases, and also the predictor factors of future cardiovascular events. Plasma biomarkers such as glucose, lipids, Homocysteine (Hcy), N-terminal pro-brain natriuretic peptide (NT-proBNP) have been shown to be involved the development of arteriosclerosis. The present study is a prospective observational and follow-up study of the characteristics of subclinical vascular disease detected by non-invasive methods that can predict progression of clinical overt vascular events in a Chinese population.MethodsThe study including both genders with age of 45 years to 75 years was designed as observational research by questionnaires and 3-year follow-up with vascular functional and structural parameters evaluation without any interventions. Questionnaire was designed to survey the lifestyle, personal history, family history of the study population. Arterial function indexes such as pulse wave velocity, cardio-ankle vascular index, flow mediated vascular dilation, ankle brachial index, carotid intima-media thickness, and plasma biomarkers such as glucose, lipids, Hcy, NT-pro BNP, Glycosylated hemoglobin, insulin resistance index, uric acid are collected. The outcome is the composite of acute myocardial infarction or coronary reperfusion therapy or stroke or peripheral vascular diseases.Conclusions2858 subjects were enrolled into our present study at baseline, and this present study will provide important information on the metabolic related traditional and new risk factors, establish a new vascular disease early detection system and scoring systems based on comprehensive vascular disease risk factors and vascular function and structure evaluation indexes.

Endothelial dysfunction in individuals born after fetal growth restriction: cardiovascular and renal consequences and preventive approaches.

Individuals born after intrauterine growth restriction (IUGR) have an increased risk of perinatal morbidity/mortality, and those who survive face long-term consequences such as cardiovascular-related diseases, including systemic hypertension, atherosclerosis, coronary heart disease and chronic kidney disease. In addition to the demonstrated long-term effects of decreased nephron endowment and hyperactivity of the hypothalamic-pituitary-adrenal axis, individuals born after IUGR also exhibit early alterations in vascular structure and function, which have been identified as key factors of the development of cardiovascular-related diseases. The endothelium plays a major role in maintaining vascular function and homeostasis. Therefore, it is not surprising that impaired endothelial function can lead to the long-term development of vascular-related diseases. Endothelial dysfunction, particularly impaired endothelium-dependent vasodilation and vascular remodeling, involves decreased nitric oxide (NO) bioavailability, impaired endothelial NO synthase functionality, increased oxidative stress, endothelial progenitor cells dysfunction and accelerated vascular senescence. Preventive approaches such as breastfeeding, supplementation with folate, vitamins, antioxidants, L-citrulline, L-arginine and treatment with NO modulators represent promising strategies for improving endothelial function, mitigating long-term outcomes and possibly preventing IUGR of vascular origin. Moreover, the identification of early biomarkers of endothelial dysfunction, especially epigenetic biomarkers, could allow early screening and follow-up of individuals at risk of developing cardiovascular and renal diseases, thus contributing to the development of preventive and therapeutic strategies to avert the long-term effects of endothelial dysfunction in infants born after IUGR.

Acute Exercise-induced Angiogenic T Cell Redistribution Is Attenuated In Older Men

Circulating CD31+ T cells (TANG) possess significant pro-angiogenic capabilities, contribute to maintenance of endothelial function, and are reduced in those with vascular-related diseases. Therefore, maintaining high levels of these cells may be important for vascular health benefits. Acute bouts of exercise stimulate an increase in circulating T-cells, including TANG cells. Ageing is associated with a chronic reduction in TANG cells. PURPOSE: To determine the influence of age on the exercise-induced increases in circulating TANG cells. METHODS: Eight young (18-25yrs) and eight older (60-75yrs) men underwent a 30-minute cycling bout at 75% of their pre-determined maximum oxygen uptake (VO2max). Peripheral blood samples were taken pre-, immediately post-, and 1 hour post-exercise. Blood samples were used to quantify circulating TANG cells by flow cytometry. TANG were defined as peripheral blood mononuclear cells expressing CD3 and CD31. In addition, these cells were further characterised using antibodies against CD4 and CD8. Mixed model repeated measures analyses of variance (ANOVA) were performed to examine the effect of age, time and interactions of such (age x time) on changes in circulating TANG cells. RESULTS: Acute exercise stimulated an increase in circulating TANG cells in both groups, with a significant time x age interaction found for total TANG cells (p=0.049), with older age group displaying reduced circulating cell response to the exercise bout (95.62±7.71% vs. 78.09±7.25%, young vs. older individuals respectively). CD4+ TANG cells were also significantly affected by acute exercise, including a time x age interaction (p=0.0014, 107.09±10.56% vs. 79.88±10.04% increase). Despite CD8+ TANG cells significantly increasing in response to exercise (time, p=0.002, 71.44±7.30% pooled increase), no such effect of age was apparent (age x time, p=0.384). CONCLUSIONS: Exercise significantly increases the number of circulating TANG cells, however ageing attenuates the increase in total TANG and CD4+ TANG cells, but not CD8+ TANG subsets. Acute increases in circulating TANG cells may contribute to the improvements in vascular function observed with exercise, yet strategies to augment the TANG cell increase to exercise in older individuals may be required to promote vascular benefits of exercise.

The effect of cognitive impairment on prosthesis use in older adults who underwent amputation due to vascular-related etiology

Older adults with amputations secondary to vascular etiologies may additionally present with cognitive impairment. Cognition plays an important role in the adoption of a prosthetic limb, although the degree and type of impact are debated. Previous literature reviews have not been directed at the specific population of older adults who underwent vascular-related lower limb amputation. First, to assess extant literature for relationships between cognitive function and prosthesis-related outcomes in older adults who underwent lower limb amputation for vascular-related etiologies. Second, to perform a critical analysis of prosthesis-related outcomes and cognitive assessments performed in the studies. Systematic literature review. A systematic review of the literature was performed in databases using keyword combinations. A total of nine articles were selected to be included in this review. Seven of the nine included studies found a relationship between decreased cognitive function and reduced performance on a prosthesis-related outcome. There were eight different prosthesis-related outcome measures, with only one study utilizing a comprehensive outcome measure. Cognitive impairment can negatively impact successful prosthesis use in older adults with lower limb amputation secondary to vascular complications. Future studies should utilize comprehensive outcome measures that represent the multifaceted constructs of cognition and prosthesis use. Clinical relevance Cognitive assessment of older adults who have undergone lower limb amputation secondary to diabetes related complications or vascular disease can be used to inform clinical decision-making. Clinicians should consider selecting prosthesis-related outcome measures that capture the full breadth of prosthesis use when evaluating patients with cognitive impairment.

Valproic acid downregulates heme oxygenase-1 independently of Nrf2 by increasing ubiquitination and proteasomal degradation

AimsHeme oxygenase-1 (HO-1; HMOX1 in human, Hmox1 in mice) is an antioxidative enzyme affecting wide range of sub-cellular processes. It was shown to modulate tumor growth or vascular-related diseases, thus being putative molecular target for tailored therapies. Therefore it is of importance to elucidate novel compounds regulating HO-1 activity/expression and to delineate mechanisms of their action. In the present study we aimed to understand mode of action of valproic acid (VA), an antiepileptic drug, on HO-1 expression. ResultsWe demonstrated that HO-1 expression is decreased by VA at protein but not mRNA level in human alveolar rhabdomyosarcoma cell line CW9019. Nrf2 transcription factor, the activator of HO-1 expression through ARE sequence, was excluded as a mediator of HO-1 decrease, as VA downregulated Bach1, a Nrf2 repressor, concomitantly upregulating ARE activation. Also miRNA-dependent inhibition was excluded as a mechanism of HMOX1 regulation. However, co-immunoprecipitation assay showed a higher level of ubiquitinated HO-1 after VA treatment. Accordingly, MG132, an inhibitor of proteasomal degradation, reversed the effect of VA on HO-1 suggesting that decrease in HO-1 expression by VA is through protein stability.The inhibitory effect of VA on HO-1 was also observed in murine cells including embryonic fibroblasts isolated from Nrf2-deficient mice, what confirms Nrf2-independent effect of the compound. Importantly, VA decreased also HO-1 expression and activity in murine skeletal muscles in vivo. ConclusionOur data indicate that VA downregulates HO-1 by acting through ubiquitin-proteasomal pathway leading to decrease in protein level.

Poly(ADP-ribose) polymerase 1 deficiency increases nitric oxide production and attenuates aortic atherogenesis through downregulation of arginase II.

Poly (ADP-ribose) polymerase (PARP) plays an important role in endothelial dysfunction, leading to atherogenesis and vascular-related diseases. However, whether PARP regulates nitric oxide (NO), a key regulator of endothelial function, is unclear so far. We investigated whether inhibition of PARP-1, the most abundant PARP isoform, prevents atherogenesis by regulating NO production and tried to elucidate the possible mechanisms involved in this phenomenon. In apolipoprotein E-deficient (apoE-/- ) mice fed a high-cholesterol diet for 12weeks, PARP-1 inhibition via treatment with 3,4-dihydro-54-(1-piperindinyl) butoxy-1(2H)-isoquinoline (DPQ) or PARP-1 gene knockout reduced aortic atherosclerotic plaque areas (49% and 46%, respectively). Both the groups showed restored NO production in mouse aortas with reduced arginase II (Arg II) expression compared to that in the controls. In mouse peritoneal macrophages and aortic endothelial cells (MAECs), PARP-1 knockout resulted in lowered Arg II expression. Moreover, phosphorylation of endothelial NO synthase (eNOS) was preserved in the aortas and MAECs when PARP-1 was inhibited. Reduced NO production in vitro due to PARP-1 deficiency could be restored by treating the MAECs with oxidized low-density lipoprotein treatment, but this effect could not be achieved with peritoneal macrophages, which was likely due to a reduction in the expression of induced NOS expression. Our findings indicate that PARP-1 inhibition may attenuate atherogenesis by restoring NO production in endothelial cells and thus by reducing Arg II expression and consequently arginase the activity.

Differentiation of mesenchymal stem cells from human amniotic fluid to vascular endothelial cells

Endothelial dysfunction is a principle feature of vascular-related disease. Endothelial cells have been acquired for the purposes of the restoration of damaged tissue in therapeutic angiogenesis. However, their use is limited by expansion capacity and the small amount of cells that are obtained. Human amniotic fluid mesenchymal stem cells (hAF-MSCs) are considered an important source for vascular tissue engineering. In this study, hAF-MSCs were characterized and then induced in order to differentiate into the endothelial-like cells. Human amniotic fluid cells (hAFCs) were obtained from amniocentesis at the second trimester of gestation. The cells were characterized as mesenchymal stem cells by flow cytometry. The results showed that the cells were positive for mesenchymal stem cell markers CD44, CD73, CD90 and HLA-ABC, and negative for CD31, Amniotic fluid stem cells marker: CD117, anti-human fibroblasts, HLA-DR and hematopoietic differentiation markers CD34 and CD45. The hAF-MSCs were differentiated into endothelial cells under the induction of vascular endothelial growth factor (VEGF) and analyzed for the expression of the endothelial-specific markers and function. The expression of the endothelial-specific markers was determined by reverse transcriptase-quantitative PCR (RT-qPCR), while immunofluorescent analysis demonstrated that the induced hAF-MSCs expressed von Willebrand factor (vWF), vascular endothelial growth factor receptor 2 (VEGFR2), CD31 and endothelial nitric oxide synthase (eNOS). The network formation assay showed that the induced hAF-MSCs formed partial networks. All results indicated that hAF-MSCs have the potential to be differentiated into endothelial-like cells, while human amniotic fluid might be a suitable source of MSCs for vascularized tissue engineering.

PGC-1α dictates endothelial function through regulation of eNOS expression.

Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1α (PGC-1α) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1α in vascular function using mice with endothelial specific loss of function (PGC-1α EC KO) and endothelial specific gain of function (PGC-1α EC TG). Here we report that endothelial PGC-1α is suppressed in angiotensin-II (ATII)-induced hypertension. Deletion of endothelial PGC-1α sensitized mice to endothelial dysfunction and hypertension in response to ATII, whereas PGC-1α EC TG mice were protected. Mechanistically, PGC-1α promotes eNOS expression and activity, which is necessary for protection from ATII-induced dysfunction as mice either treated with an eNOS inhibitor (LNAME) or lacking eNOS were no longer responsive to transgenic endothelial PGC-1α expression. Finally, we determined that the orphan nuclear receptor, estrogen related receptor α (ERRα) is required to coordinate the PGC-1α -induced eNOS expression. In conclusion, endothelial PGC-1α expression protects from vascular dysfunction by promoting NO• bioactivity through ERRα induced expression of eNOS.

Nutraceuticals in hypercholesterolaemia: an overview.

Growing attention is now being given to the possible preventive/alternative ways to avoid illness onset. Changes in lifestyle and food habits are taking over from the conventional pharmaceutical‐based approach, especially for chronic pathologies. Nutraceuticals have been proposed as key tools for the prevention and cure of some pathological conditions. This is leading research to develop new formulations based on these pharma‐foods addressed in a specific way to prevent and cure health issues, which, in turn, will have an effect on therapy‐related costs sustained by any National Health Organization. According to existing regulations, nutraceuticals cannot be categorized as either food or drugs but, by definition, often inhabit a grey area in between the two, being assimilated into food supplements, notwithstanding the beneficial properties that they can provide for some pathological conditions. A nutraceuticals‐based approach for health management, in particular for some pathological conditions, has resulted in a worldwide growing ‘nutraceutical’ revolution. An outstanding example is the approach to the ‘metabolic syndrome’, which includes overweight, obesity and cardiovascular‐related diseases, causing a sort of cascade of chronic health conditions, which is becoming a norm in modern life. Hypercholesterolaemia is one of these. It represents an example of a pathology that can be linked to both a poor lifestyle and dietary habits. The nutraceutical approach to hypercholesterolaemia is described in the present review as a possible alternative to the conventional drug‐based therapy.Linked ArticlesThis article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc

Relationship between cardio-ankle vascular index and homocysteine in hypertension subjects with hyperhomocysteinemia

ABSTRACTBackground: Arteriosclerosis evaluated by arterial stiffness is the basic pathophysiological change during the development of hypertension. Cardio-ankle vascular index (CAVI) is an index of arterial stiffness. Hyperhomocysteinemia (HHcy) is an independent risk factor for vascular diseases. However, there was little research about the relationship between CAVI and homocysteine (Hcy) in hypertension subjects with HHcy. Methods: A total of 330 subjects (M/F 133/197) from Vascular Medicine of Peking University Shougang Hospital were divided into four groups: control group (group 1, normotensive with normal Hcy, n = 149), hypertension group (group 2, n = 113), HHcy group (group 3, n = 30), and hypertension with HHcy group (group 4, n = 38). CAVI was measured by VS-1000 apparatus. Results: Our results showed that CAVI was significantly higher in group 4 than in group 1 and group 2 (8.41 ± 1.08 vs. 7.79 ± 1.14; 8.41 ± 1.08 vs. 7.87 ± 1.02, both p < 0.05, respectively). Positive correlation between CAVI and Hcy was found in the entire study group (r = 0.109, p = 0.049) and hypertension subjects (group 2 + group 4; r = 0.202, p = 0.014). Multivariate analysis showed that Hcy was an independent associating factor of CAVI in all subjects (β = 0.251, p = 0.034). Conclusions: The present study showed that CAVI was significantly higher in hypertension subjects with HHcy compared to hypertension group. There was significant correlation between CAVI and Hcy, indicating the relationship between arterial stiffness and biomarkers in vascular-related diseases.

Clinically relevant timing of antenatal sildenafil treatment reduces pulmonary vascular remodeling in congenital diaphragmatic hernia.

Patients with congenital diaphragmatic hernia (CDH) suffer from severe pulmonary hypertension attributable to altered development of the pulmonary vasculature, which is often resistant to vasodilator therapy. Present treatment starts postnatally even though significant differences in the pulmonary vasculature are already present early during pregnancy. We examined the effects of prenatal treatment with the phosphodiesterase-5 inhibitor sildenafil on pulmonary vascular development in experimental CDH starting at a clinically relevant time. The well-established, nitrofen-induced CDH rodent model was treated daily with 100 mg/kg sildenafil from day 17.5 until day 20.5 of gestation (E17.5-20.5). Importantly, this timing perfectly corresponds to the developmental stage of the lung at 20 wk of human gestation, when CDH is detectable by 2D-ultrasonography and/or MRI. At E21.5 pups were delivered by caesarean section and euthanized by lethal injection of pentobarbital. The lungs were isolated and subsequently analyzed using immunostaining, real-time PCR, and volume measurements. Prenatal treatment with sildenafil improved lung morphology and attenuated vascular remodeling with reduced muscularization of the smaller vessels. Pulmonary vascular volume was not affected by sildenafil treatment. We show that prenatal treatment with sildenafil within a clinically relevant period improves pulmonary vascular development in an experimental CDH model. This may have important implications for the management of this disease and related pulmonary vascular diseases in human.

Harnessing the Therapeutic Potential of Capsaicin and Its Analogues in Pain and Other Diseases.

Capsaicin is the most predominant and naturally occurring alkamide found in Capsicum fruits. Since its discovery in the 19th century, the therapeutic roles of capsaicin have been well characterized. The potential applications of capsaicin range from food flavorings to therapeutics. Indeed, capsaicin and few of its analogues have featured in clinical research covered by more than a thousand patents. Previous records suggest pleiotropic pharmacological activities of capsaicin such as an analgesic, anti-obesity, anti-pruritic, anti-inflammatory, anti-apoptotic, anti-cancer, anti-oxidant, and neuro-protective functions. Moreover, emerging data indicate its clinical significance in treating vascular-related diseases, metabolic syndrome, and gastro-protective effects. The dearth of potent drugs for management of such disorders necessitates the urge for further research into the pharmacological aspects of capsaicin. This review summarizes the historical background, source, structure and analogues of capsaicin, and capsaicin-triggered TRPV1 signaling and desensitization processes. In particular, we will focus on the therapeutic roles of capsaicin and its analogues in both normal and pathophysiological conditions.

Estrogen and promoter methylation in the regulation of PLA2G7 transcription

In the current study, cell lines including HEK293, SW480, HPASMC, HPCASMC and HAEC were cultured with 5-aza-2-deoxycytidine (DAC) and 17-β-estradiol to investigate whether PLA2G7 transcription was under the control of promoter methylation and 17-β-estradiol. Luciferase reporter gene assays were used to evaluate whether reporter gene activity was enhanced by PLA2G7 promoter fragment. Gene expression and methylation were detected using RT-PCR and pyrosequencing methods, respectively. Endogenous PLA2G7 transcription levels were found to be significantly lower in vascular related cell lines than in the other cell lines. Luciferase reporter gene assays indicated that gene activity was significantly enhanced by PLA2G7 promoter fragment. PLA2G7 transcription was found to be up-regulated with the treatment of DAC. The 17-β-estradiol was found to down-regulate PLA2G7 transcription in all the cell lines. However, 17-β-estradiol did not have significant effect on PLA2G7 methylation. Further chromatin immunoprecipitation assay showed that 17-β-estradiol might regulate gene transcription by affecting the acetylated histone H3 and H4 marks on PLA2G7 promoter. Our results showed that PLA2G7 gene expression was co-regulated by 17-β-estradiol and promoter methylation. Our findings might provide molecular clues for gender disparity in the contribution of PLA2G7 to vascular related diseases such as coronary heart disease.

Abstract 322: In Vivo Vibrational Photoacoustic Tomography of Perivascular Fat in Apolipoprotein E-Deficient Mice

Vibrational Photoacoustic Tomography (VPAT) is an emerging imaging modality that utilizes pulsed laser light to induce acoustic waves and obtain tissue specific compositional information. When used in combination with ultrasound, VPAT has the potential to identify the location, size, and distribution of lipids in vivo . In our study, we hypothesized that VPAT can be used to distinguish perivascular aortic fat accumulation between apolipoprotein E-deficient (apoE -/- ) and wild-type (WT) mice. A 40 MHz central frequency transducer (Vevo2100, VisualSonics) and a ND:YAG pulsed laser (NT352C, Ekspla) were used to simultaneously obtain both long axis in vivo B-mode and VPAT images of the infrarenal aorta in three apoE -/- (8.7±0 months old) and WT controls (2.9±0 months old) mice. Pulsed laser light was specifically tuned to 1100nm and 1210nm to image blood and lipid, respectively. We then measure perivascular lipid thickness in three distinct locations along the anterior wall of the aorta. These measurements were then averaged to obtain a final perivascular fat thickness score for both the apoE -\- and WT groups. We observed greater 1210 nm signal in apoE -/- (0.47±0.14 mm) mice versus WT mice (0.32±0.11 mm; p&lt;0.05), suggesting that apoE -/- mice have greater perivascular lipid accumulation than WT controls. These findings are significant as they show that VPAT can be used to image and track lipid accumulation in vivo . Future work will focus on monitoring luminal plaque progression in atherosclerotic murine models, including hypercholesterolemic mice on a high fat diet or rodent models of severe carotid stenosis. If successful, VPAT has the potential to be used in the clinic to 1) study atherosclerosis plaque development, 2) evaluate the effectiveness of prospective therapeutics, and 3) improve the diagnosis of atherosclerosis or related vascular diseases.

Abstract 553: The Matricellular Protein Ccn1 is a Key Mediator of Smooth Muscle Cell Migration and Neointimal Formation

Platelet-derived growth factor (PDGF), a potent chemoattractant, induces smooth muscle cell (SMC) migration via the MAPK and PI3K/Akt pathways. However, the downstream mediators are still elusive. In particular, the role of extracellular mediators is largely unknown. In this study, we identified the matricellular protein CCN1, which is de novo synthesized in response to PDGF stimulation, as the key downstream mediator of the ERK and JNK pathways, independent of the p38 MAPK and AKT pathways, and, thereby, it mediates PDGF-induced SMC migration. Our results revealed that, when CCN1 was newly synthesized by PDGF, it was promptly translocated to the extracellular matrix and physically interacted with the plasma membrane integrins α6β1 and αvβ3. We further demonstrate that CCN1 and integrins are integral components of the PDGF signaling pathway via an “outside-in” signaling route to activate intracellular focal adhesion kinase (FAK), leading to SMC migration. Therefore, our study provides new evidence that the PDGF-induced endogenous extracellular matrix component CCN1 is a key mediator in modulating SMC migration by connecting intracellular PDGF-ERK and JNK signals with integrin/FAK signaling. Therefore, extracellular CCN1 convergence with growth factor signaling and integrin/FAK signaling is a new concept of growth factor-induced cell migration. We further identified that CCN1 is a key mediator of lysophosphatidic acid (LPA)-mediated SMC migration. Our recent data reveal that CCN1 mediates LPA-induced neointimal formation. The discovered novel signaling pathway may represent an important therapeutic target in growth factor/lipid-mediated cell migration related vascular diseases.

Low dose tranexamic acid reduces blood transfusion rate after total knee arthroplasty: A population-based study in Taiwan.

Previous reports, mostly small clinical trials conducted in USA or Europe, indicated that tranexamic acid (TXA) would be effective for reducing blood transfusions after total knee arthroplasty (TKA). However, large scale studies are needed regarding the effectiveness and safety issue of complication events following TKA, especially for the Asian population. We aimed to evaluate the efficacy and safety of TXA use based on data from an elderly population in Taiwan. This was a retrospective population-based study using an inpatient dataset from the nationwide health insurance research database in Taiwan. Patients aged >65years with a diagnosis of osteoarthritic knee in 2012 were included (n=10,321). A low-dose intravenous form of TXA (250-1000mg) was identified perioperatively during the TKA. The surgical outcomes of interest were allogeneic red blood cell transfusion and postoperative 30-day complications. A total of 1205 (11.7%) patients received TXA. Based on a multilevel logistic regression model, we found a 47% odds reduction of blood transfusion without elevating the complications of infection and vascular-related diseases. Furthermore, the drug effect in reducing transfusion was different among hospital levels, and medical centers had a relatively lower transfusion rate. The use of perioperative TXA was an efficient strategy to prevent blood loss after TKA.