Ryohei Ishii

Interleukin-16 Promotes Cardiac Fibrosis and Myocardial Stiffening in Heart Failure with Preserved Ejection Fraction

Background Chronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction (HFpEF) is observed in half of all patients with CHF and carries the same poor prognosis as CHF with reduced LV ejection fraction (HFrEF). In contrast to HFrEF, there is no established therapy for HFpEF. Chronic inflammation contributes to cardiac fibrosis, a crucial factor in HFpEF; however, inflammatory mechanisms and mediators involved in the development of HFpEF remain unclear. Therefore, we sought to identify novel inflammatory mediators involved in this process. Methods and Results An analysis by multiplex-bead array assay revealed that serum interleukin-16 (IL-16) levels were specifically elevated in patients with HFpEF compared with HFrEF and controls. This was confirmed by enzyme-linked immunosorbent assay in HFpEF patients and controls, and serum IL-16 levels showed a significant association with indices of LV diastolic dysfunction. Serum IL-16 levels were also elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in the HFpEF rat model. Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension. Conclusion Our data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

Association study of KIBRA gene with memory performance in a Japanese population

Abstract Objectives. Papassotiropoulos et al. (Science 314: p 475) discovered that a single nucleotide polymorphism (SNP) of the KIBRA gene (rs17070145) was associated with delayed recall performance in Caucasians. KIBRA is highly expressed in the brain and kidneys, and is reported to be involved in synaptic plasticity. Therefore, we first tried to replicate the association between the SNP and memory performance in a Japanese subjects. Methods. We examined the association between the SNP and memory performance measured by the Wechsler Memory Scale-Revised (WMS-R) in 187 healthy Japanese people. Results. The T allele carriers had significantly better verbal memory, attention/concentration and delayed recall performance than the C/C carriers (corrected P = 0.044, 0.047 and 0.0084, respectively). Furthermore, the C/T carriers and the T/T carriers had better delayed recall performance than the C/C carriers (post hoc P = 0.0017 and 0.0096). Conclusions. This data suggest that the C/C genotype might have an impact on memory performance in Asian populations as well as in Caucasian populations. Further investigation to clarify the association of the KIBRA gene with memory in other ethnic groups is warranted.

A novel heart failure mice model of hypertensive heart disease by angiotensin II infusion, nephrectomy, and salt loading

Although the mouse heart failure (HF) model of hypertensive heart disease (HHD) is useful to investigate the pathophysiology and new therapeutic targets for HHD, the model using simple experimental procedures and stable phenotypes has not been established. This study aimed to develop a novel mouse HF model of HHD by combining salt loading and uninephrectomy with ANG II infusion. Eight-week-old C57BL/6 male mice were treated with ANG II infusion (AT), ANG II infusion and uninephrectomy (AN), ANG II infusion and salt loading (AS), or ANG II infusion, uninephrectomy, and salt loading (ANS). Systolic blood pressure was significantly elevated and left ventricular (LV) hypertrophy was found in AT, AN, AS, and ANS mice, and there were no significant differences in those parameters between the four groups. At 6 wk after the procedures, only ANS mice showed significant decreases in LV fractional shortening and increases in lung weight with a high incidence. This phenotype was reproducible, and there were few perioperative or early deaths in the experimental procedures. Severe LV fibrosis was found in ANS mice. Oxidative stress was enhanced and small GTPase Rac1 activity was upregulated in the hearts of ANS mice. After the addition of salt loading and uninephrectomy to the ANG II infusion mouse model, cardiac function was significantly impaired, and mice developed HF. This might be a novel and useful mouse HF model to study the transition from compensated LV hypertrophy to HF in HHD.

Balloon type elasticity sensing for left ventricle of small laboratory animal

This paper describes an elasticity sensing system for left ventricle of small laboratory animal. We first show the basic concept of the proposed method, where a ring shaped specimen is dilated by a balloon type probe using a pressure based control, and the elasticity of the specimen is estimated by using the stress and strain information. We introduce a dual cylinder model for approximating the strengths of the specimens material and the balloon. Based on this model, we can derive Youngs modulus of the specimen. After explaining the developed experimental system, we show a couple of experimental results using rats and mice, where HFPEF (Heart Failure Preserved Ejection Fraction) group can be distinguished from a normal group.

Two-channel near infrared spectroscopy activation curves of oxyhemoglobin during frontal tasks in schizophrenia

ferent developmental stages. In the present study, a comprehensive battery of behavioral tasks was applied to longitudinally characterize behavioral phenotypes in NRG1 and wild-type mice. All NRG1 heterozygous mice and their wild-type littermate controls were generated from NRG1 heterozygous breeding pairs. A battery of behavioral tasks (including locomotor activity, hole broad, elevated plus maze, object recognition, social preference test, two-bottle sucrose preference, pre-pulse inhibition, hot plate, and trace fear conditioning) was performed sequentially on the same batch of male and female mice in 2 months of age (postnatal day 63–81) and 6 months of age (postnatal day 189–210). Our preliminary data revealed that NRG1 mutant mice displayed an overall normal behavioral profile in these 2 ages. However, NRG1 deficient females exhibited hyperactivity in the open field in the age of 6 months compared with their wild-type controls. These preliminary findings suggest that NRG1 deficiency might have minor impact on basal behaviors. Further experiments are in progress.