Tomoko Nakao

VEGF‐A induces its negative regulator, soluble form of VEGFR‐1, by modulating its alternative splicing

Vascular endothelial growth factor‐A (VEGF‐A) is one of the major angiogenic factors, and its actions are primarily mediated through its two membrane receptors, VEGFR‐1 and VEGFR‐2. A soluble form of VEGFR‐1 (sVEGFR‐1) sequesters the free form of VEGF‐A, and acts as a potent anti‐angiogenic factor. While sVEGFR‐1 is synthesized as a splice variant of VEGF‐R1 gene, the interactions between VEGF‐A and sVEGFR‐1 remain largely unknown. Here, we show that VEGF‐A upregulates sVEGF‐R1 expression in human vascular endothelial cells but leaves full‐length VEGF‐R1 expression unchanged, and that this induction was dependent on the VEGFR‐2‐protein kinase C‐MEK signaling pathway. The VEGF‐A‐induced sVEGFR‐1 upregulation can operate as a negative feedback system, which if modulated can become a novel therapeutic target for regulating pathological angiogenesis.

Melatonin ameliorates Angiotensin II-induced vascular endothelial damage via its antioxidative properties

Melatonin is well known to have a beneficial effect on the cardiovascular system, but it remains to be elucidated whether melatonin has a therapeutic effect on the vascular damage induced by the potential vasoactive substance angiotensin II (Ang II). In this study, the effects of melatonin on Ang II‐induced vascular endothelial damage were investigated. In cultured vascular endothelial cells, Ang II stimulation increased ROS generation and inhibited eNOS phosphorylation (Ser1177), both of which were clearly restored by pretreatment with melatonin. The translocation of p47phox subunit of NADPH oxidase from the cytosol to plasma membrane was promoted in Ang II‐treated vascular endothelial cells, which was canceled by melatonin pretreatment. In Ang II‐infused rats, increased ROS generation in the aortic wall and impaired endothelial function of the aortic ring were observed, which were rescued by coadministration of melatonin. In vasculature, melatonin receptor agonist ramelteon had the antioxidative effect in the same manner as melatonin by itself. These findings suggest that melatonin directly ameliorates Ang II‐induced vascular endothelial damage partly via its antioxidative properties, providing with us the potential rationale for clinical application of melatonin to the prevention from cardiovascular diseases.

Angiotensin II impairs endothelial nitric-oxide synthase bioavailability under free cholesterol-enriched conditions via intracellular free cholesterol-rich membrane microdomains.

Background: Free cholesterol forms membrane microdomains in endothelial cells. Results: Free cholesterol loading formed intracellular vesicles with free cholesterol-rich microdomains that were shifted toward late endosomes/lysosomes by angiotensin II, resulting in impairment of endothelial NOS availability. Conclusion: Angiotensin II decreased the bioavailability of endothelial NOS in a free cholesterol-enriched condition. Significance: Free cholesterol-rich microdomains are crucial platforms of endothelial NOS availability. Vascular endothelial function is impaired in hypercholesterolemia partly because of injury by modified LDL. In addition to modified LDL, free cholesterol (FC) is thought to play an important role in the development of endothelial dysfunction, although the precise mechanisms remain to be elucidated. The aim of this study was to clarify the mechanisms of endothelial dysfunction induced by an FC-rich environment. Loading cultured human aortic endothelial cells with FC induced the formation of vesicular structures composed of FC-rich membranes. Raft proteins such as phospho-caveolin-1 (Tyr-14) and small GTPase Rac were accumulated toward FC-rich membranes around vesicular structures. In the presence of these vesicles, angiotensin II-induced production of reactive oxygen species (ROS) was considerably enhanced. This ROS shifted endothelial NOS (eNOS) toward vesicle membranes and vesicles with a FC-rich domain trafficked toward perinuclear late endosomes/lysosomes, which resulted in the deterioration of eNOS Ser-1177 phosphorylation and NO production. Angiotensin II-induced ROS decreased the bioavailability of eNOS under the FC-enriched condition.

Evaluation of Right Ventricle by Speckle Tracking and Conventional Echocardiography in Rats With Right Ventricular Heart Failure

Speckle tracking echocardiography (STE) has been reported to be a promising technique for evaluating right ventricular (RV) function in the clinical setting. On the other hand, the usefulness of STE for RV evaluation in small animal models has not been clarified, although the rat model is among the most commonly used animal models to develop novel effective treatments against pulmonary hypertension and RV heart failure (HF).We validated the use of STE and conventional echocardiographic variables for evaluating RV functions in a rat model by comparing the echocardiographic values of RVHF rats (n = 12) induced by monocrotaline injection with those of control rats (n = 12).Most conventional echocardiographic variables demonstrated that RVHF rats have significant RV dysfunction. The area under the curve (AUC) values to distinguish RV dysfunction in RVHF rats from normal RV function in control rats using fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), RV myocardial performance index (MPI), peak tissue Doppler tricuspid annular velocities at systole (Sa), and at early diastole (Ea) were 0.71, 0.98, 0.79, 0.92, and 0.91, respectively. However, using STE analysis for RV evaluation, limited reproducibility was observed (variability 19-37 %, ICC 0.74-0.88) and the only circumferential strain showed significantly lower absolute values (P = 0.039, AUC = 0.76).To evaluate RV function in rat models, circumferential strain may be useful, however, the reproducibility and diagnostic utility were limited. Conventional echocardiographic variables such as TAPSE, tissue Doppler Sa, and Ea have superior diagnostic utility.

Relationship of Left Ventricular Diastolic Function to Obesity and Overweight in a Japanese Population With Preserved Left Ventricular Ejection Fraction

BACKGROUND Obesity has been found to be associated with future development of diastolic heart failure. Other evidence has indicated that the effect of obesity on left ventricular (LV) mass varies among ethnicities. However, there are few data on the relationship between body mass index (BMI) and LV diastolic dysfunction in the Japanese population. METHODSANDRESULTS We performed echocardiography in 788 subjects without valvular disease or LV systolic dysfunction. They were divided into 3 groups by BMI: normal weight, overweight, and obese. We used multivariable linear regression analysis to assess the clinical variables associated with diastolic parameters, including BMI. We also assessed the risk of diastolic dysfunction associated with BMI using multivariable logistic models. Overweight and obese subjects had significantly worse LV diastolic function and greater LV mass than normal weight subjects. In the multivariable analysis, BMI was independently associated with diastolic parameters. Furthermore, after adjusting for clinical factors, the increased risks of diastolic dysfunction in overweight subjects (adjusted odds ratio: 2.02, 95% confidence interval 1.21-3.36) and obese subjects (4.85, 3.36-16.27) were greater than those previously observed in Western populations. CONCLUSIONS The Japanese population might be more susceptible than Western subjects to the effect of BMI on LV diastolic function. Differences between ethnicities should be taken into consideration in strategies for the prevention of diastolic heart failure. (Circ J 2016; 80: 1951-1956).

Improvement of endothelial function in parallel with the amelioration of dry cough and dyspnea due to interstitial pneumonia by intravenous cyclophosphamide pulse therapy in patients with systemic sclerosis : a preliminary report of two cases

Intravenous cyclophosphamide pulse therapy (IVCY) exerts its efficacy against interstitial lung disease (ILD) associated with systemic sclerosis (SSc) by restoring vascular injuries as well as aberrant immune activation. We recently experienced two patients with SSc-ILD in whom the values of brachial flow-mediated dilation (FMD) reflected the efficacy of IVCY. We herein report the details of these cases and discuss the potential of FMD to predict and evaluate the effect of IVCY on SSc-ILD.

Ultrathin endoscope flexibility can predict discomfort associated with unsedated transnasal esophagogastroduodenoscopy

AIM To evaluate the effects of choice of insertion route and ultrathin endoscope types. METHODS This prospective study (January-June 2012) included 882 consecutive patients who underwent annual health checkups. Transnasal esophagogastroduodenoscopy (EGD) was performed in 503 patients and transoral EGD in 235 patients using six types of ultrathin endoscopes. Patients were given a choice of insertion route, either transoral or transnasal, prior to EGD examination. For transoral insertion, the endoscope was equipped with a thin-type mouthpiece and tongue depressor. Conscious sedation was not used for any patient. EGD-associated discomfort was assessed using a visual analog scale (VAS; no discomfort 0- maximum discomfort 10). RESULTS Rates of preference for transnasal insertion were significantly higher in male (male/female 299/204 vs 118/117) and younger patients (56.8 ± 11.2 years vs 61.3 ± 13.0 years), although no significant difference was found in VAS scores between transoral and transnasal insertion (3.9 ± 2.3 vs 4.1 ± 2.5). Multivariate analysis revealed that gender, age, operator, and endoscope were independent significant predictors of VAS for transnasal insertion, although gender, age, and endoscope were those for transoral insertion. Further analysis revealed only the endoscopic flexibility index (EFI) as an independent significant predictor of VAS for transnasal insertion. Both EFI and tip diameter were independent significant predictors of VAS for transoral insertion. CONCLUSION Flexibility of ultrathin endoscopes can be a predictor of EGD-associated discomfort, especially in transnasal insertion.

A Food-Derived Flavonoid Luteolin Protects against Angiotensin II-Induced Cardiac Remodeling

Oxidative stress has been implicated in cardiac remodeling (cardiac fibrosis and hypertrophy), which impairs cardiac function and metabolism; therefore, it is anticipated antioxidative compounds will have protective properties against cardiac remodeling. Luteolin (3’,4’,5,7-tetrahydroxyflavone), a widely distributed flavonoid found in many herbal extracts including celery, green pepper, perilla leaves and seeds, and chamomile, is a known to be a potent antioxidant and was previously demonstrated to exert an antifibrotic effect in the lungs and the liver. In this study, we clearly demonstrate that oral pretreatment with the higher-luteolin diet (0.035% (wt/wt)) protected against cardiac fibrosis and hypertrophy as well as a hyperoxidative state in Ang II-infused rats. In cardiac tissue, increased gene expression levels of TGFβ1, CTGF, Nox2, Nox4, ANP, and BNP induced by Ang II were restored by oral pretreatment of this high-luteolin diet. In cultured rat cardiac fibroblasts, H2O2-induced TGFβ1 expression and the phosphorylation of JNK were suppressed by luteolin pretreatment. In conclusion, food-derived luteolin has protective actions against Ang II-induced cardiac remodeling, which could be mediated through attenuation of oxidative stress.

Factors influencing left atrial volume in a population with preserved ejection fraction: Left ventricular diastolic dysfunction or clinical factors?

BACKGROUND Increased left atrial volume (LAV) predicts a higher incidence of cardiovascular events and is widely recognized as a major surrogate marker of left ventricular (LV) diastolic dysfunction (DD). Although the pathophysiology of LA enlargement is probably multifactorial, few studies have examined comprehensively the clinical factors that lead to LA enlargement in the absence of valvular disease or LV systolic dysfunction. Therefore, we investigated associations between LAV and several clinical and echocardiographic parameters including DD. METHODS We enrolled 557 subjects without significant valve disease or LV systolic dysfunction from the health check-up clinic retrospectively. We performed univariable and multivariable linear regression using lnLAV index as the dependent variable and the following independent variables: gender, age, smoking status, drinking habit, hypertension, diabetes, body mass index (BMI), LV ejection fraction, DD, LV mass index, hemoglobin, serum creatinine, serum total cholesterol, serum uric acid, serum sodium, and serum iron. RESULTS In multivariable analysis, LAV index was independently associated with BMI, lower hemoglobin, and moderate and severe DD compared with normal diastolic function (p<0.001), but not with mild DD (p=0.70). CONCLUSIONS LA enlargement was independently associated with moderate and severe DD, but not with mild DD. Furthermore, obesity and lower hemoglobin were associated with LAV independently of DD.

Prognostic impact of venous thromboembolism in patients with Duchenne muscular dystrophy: Prospective multicenter 5-year cohort study

Please cite this article as: Kimura Koichi, Morita Hiroyuki, Daimon Masao, Kawata Takayuki, Nakao Tomoko, Lee Seitetsu L., Hirokawa Megumi, Ebihara Aya, Nakajima Takashi, Ozawa Tetsuo, Yonemochi Yosuke, Aida Izumi, Motoyoshi Yasufumi, Mikata Takashi, Uchida Idai, Komori Tetsuo, Kitao Ruriko, Nagata Tetsuya, Takeda Shin’ichi, Komaki Hirofumi, Segawa Kazuhiko, Takenaka Katsu, Komuro Issei, Prognostic Impact of Venous Thromboembolism in Patients with Duchenne Muscular Dystrophy: Prospective Multicenter 5-Year Cohort Study, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.04.244