研究者詳細 - 神津　英至

論文 - 神津　英至

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mRNA結合蛋白質トリステトラプロリンはミトコンドリア機能調節による鉄欠乏に対する心臓応答に必須である【JST・京大機械翻訳】

Sato Tatsuya, Chang Hsiang-Chun, Bayeva Marina, Shapiro Jason S., Ramos-Alonso Lucia, Kouzu Hidemichi, Jiang Xinghang, Liu Ting, Yar Sumeyye, Sawicki Konrad T., Chen Chunlei, Martinez-Pastor Maria Teresa, Stumpo Deborah J., Schumacker Paul T., Blackshear Perry J., Ben-Sahra Issam, Puig Sergi, Ardehali Hossein

Proceedings of the National Academy of Sciences of the United States of America 115 ( 27 ) E6291-E6300 2018年07月 [国際誌]

Cells respond to iron deficiency by activating iron-regulatory proteins to increase cellular iron uptake and availability. However, it is not clear how cells adapt to conditions when cellular iron uptake does not fully match iron demand. Here, we show that the mRNA-binding protein tristetraprolin (TTP) is induced by iron deficiency and degrades mRNAs of mitochondrial Fe/S-cluster-containing proteins, specifically Ndufs1 in complex I and Uqcrfs1 in complex III, to match the decrease in Fe/S-cluster availability. In the absence of TTP, Uqcrfs1 levels are not decreased in iron deficiency, resulting in nonfunctional complex III, electron leakage, and oxidative damage. Mice with deletion of Ttp display cardiac dysfunction with iron deficiency, demonstrating that TTP is necessary for maintaining cardiac function in the setting of low cellular iron. Altogether, our results describe a pathway that is activated in iron deficiency to regulate mitochondrial function to match the availability of Fe/S clusters.

DOI PubMed J-GLOBAL

miR-301bによる翻訳調節は糖尿病心臓におけるAMPデアミナーゼをアップレギュレートする【JST・京大機械翻訳】

Tatekoshi Yuki, Tanno Masaya, Kouzu Hidemichi, Abe Koki, Miki Takayuki, Kuno Atsushi, Kuno Atsushi, Yano Toshiyuki, Ishikawa Satoko, Ohwada Wataru, Sato Tatsuya, Sato Tatsuya, Niinuma Takeshi, Suzuki Hiromu, Miura Tetsuji

Journal of Molecular and Cellular Cardiology 119 138 - 146 2018年06月 [国際誌]

AMP deaminase (AMPD) plays a crucial role in adenine nucleotide metabolism. Recently we found that upregulated AMPD activity is associated with ATP depletion and contractile dysfunction under the condition of pressure overloading in the heart of a rat model of type 2 diabetes mellitus (T2DM), OLETF. Here we examined the mechanism of AMPD upregulation by T2DM. The protein level of 90-kDa full-length AMPD3 was increased in whole myocardial lysates by 55% in OLETF compared to those in LETO, a non-diabetic control. In contrast, the mRNA levels of AMPD3 in the myocardium were similar in OLETF and LETO. AMPD3 was comparably ubiquitinated in OLETF and LETO, and its degradation ex vivo was more sensitive to MG-132, a proteasome inhibitor, in OLETF than in LETO. MicroRNA array analysis revealed downregulation (>50%) of 57 microRNAs in OLETF compared to those in LETO, among which miR-301b was predicted to interact with the 3'UTR of AMPD3 mRNA. AMPD3 protein level was significantly increased by a miR-301b inhibitor and was decreased by a miR-301b mimetic in H9c2 cells. A luciferase reporter assay confirmed binding of miR-301b to the 3'UTR of AMPD3 mRNA. Transfection of neonatal rat cardiomyocytes with a miR-301b inhibitor increased 90-kDa AMPD3 and reduced ATP level. The results indicate that translational regulation by miR-301b mediates upregulated expression of cardiac AMPD3 protein in OLETF, which potentially reduces the adenine nucleotide pool at the time of increased work load. The miR-301b-AMPD3 axis may be a novel therapeutic target for intervening enegy metabolism in diabetic hearts.

DOI PubMed J-GLOBAL

Corrigendum: Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling.

Amy K Rines, Hsiang-Chun Chang, Rongxue Wu, Tatsuya Sato, Arineh Khechaduri, Hidemichi Kouzu, Jason Shapiro, Meng Shang, Michael A Burke, Eltyeb Abdelwahid, Xinghang Jiang, Chunlei Chen, Tenley A Rawlings, Gary D Lopaschuk, Paul T Schumacker, E Dale Abel, Hossein Ardehali

Nature communications 8 16155 - 16155 2017年08月 [国際誌]

インターネット上から得たシブトラミンにより生じた心臓停止:体外式膜型人工肺を用いて蘇生に成功した心血管疾患既往の無い若い女性症例

Bunya Naofumi, Sawamoto Keigo, Uemura Shuji, Kyan Ryoko, Inoue Hiroyuki, Nishida Junichi, Kouzu Hidemichi, Kokubu Nobuaki, Miura Tetsuji, Narimatsu Eichi

Acute Medicine & Surgery (Web) ( (一社)日本救急医学会 ) 4 ( 3 ) 334 - 337 2017年07月 [国際誌]

Case: Sibutramine is a weight loss agent that was withdrawn from the market in the USA and European Union because it increases adverse events in patients with cardiovascular diseases. However, non-prescription weight loss pills containing sibutramine can be still easily purchased over the Internet. A 21-year-old woman without history of cardiovascular diseases developed cardiac arrest. She was a user of a weight loss pills, containing sibutramine and hypokalemia-inducing agents, imported from Thailand over the Internet. Outcome: She was successfully resuscitated without any neurological deficits by using extracorporeal membrane oxygenation for refractory ventricular fibrillation. Conclusion: This case indicates that sibutramine can cause cardiac arrest even in subjects without pre-existing cardiovascular disease when combined with agents that promote QT prolongation.

DOI PubMed J-GLOBAL

Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55α contributes to enlargement of infarct size by chronic kidney disease.

Toshiyuki Tobisawa, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Yukishige Kimura, Satoko Ishikawa, Hidemichi Kouzu, Keitaro Nishizawa, Hideaki Yoshida, Tetsuji Miura

Basic research in cardiology 112 ( 3 ) 31 - 31 2017年05月 [国際誌]

Chronic kidney disease (CKD) increases myocardial infarct size by an unknown mechanism. Here we examined the hypothesis that impairment of protective PI3K-PDK1-Akt and/or mTORC-Akt signaling upon reperfusion contributes to CKD-induced enlargement of infarct size. CKD was induced in rats by 5/6 nephrectomy (SNx group) 4 weeks before myocardial infarction experiments, and sham-operated rats served as controls (Sham group). Infarct size as a percentage of area at risk after ischemia/reperfusion was significantly larger in the SNx group than in the Sham group (56.3 ± 4.6 vs. 41.4 ± 2.0%). In SNx group, myocardial p-Akt-Thr308 level at baseline was elevated, and reperfusion-induced phosphorylation of p-Akt-Ser473, p-p70s6K and p-GSK-3β was significantly suppressed. Inhibition of Akt-Ser473 phosphorylation upon reperfusion by Ku-0063794 significantly increased infarct size in the Sham group but not in the SNx group. There was no difference between the two groups in activities of mTORC2 and PDK1 and protein level of PTEN. However, the PP2A regulatory subunit B55α, which specifically targets Akt-Thr308, was reduced by 24% in the SNx group. Knockdown of B55α by siRNA increased baseline p-Akt-Thr308 and blunted Akt-Ser473 phosphorylation in response to insulin-like growth factor-1 (IGF-1) in H9c2 cells. A blunted response of Akt-Ser473 to IGF-1 was also observed in HEK293 cells transfected with a p-Thr308-mimetic Akt mutant (T308D). These results indicate that increased Akt-Thr308 phosphorylation by down-regulation of B55α inhibits Akt-Ser473 phosphorylation upon reperfusion in CKD and that the impaired Akt activation by insufficient Ser473 phosphorylation upon reperfusion contributes to infarct size enlargement by CKD.

Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling.

Amy K Rines, Hsiang-Chun Chang, Rongxue Wu, Tatsuya Sato, Arineh Khechaduri, Hidemichi Kouzu, Jason Shapiro, Meng Shang, Michael A Burke, Eltyeb Abdelwahid, Xinghang Jiang, Chunlei Chen, Tenley A Rawlings, Gary D Lopaschuk, Paul T Schumacker, E Dale Abel, Hossein Ardehali

Nature communications 8 14095 - 14095 2017年01月 [国際誌]

Ischaemic heart disease limits oxygen and metabolic substrate availability to the heart, resulting in tissue death. Here, we demonstrate that the AMP-activated protein kinase (AMPK)-related protein Snf1-related kinase (SNRK) decreases cardiac metabolic substrate usage and mitochondrial uncoupling, and protects against ischaemia/reperfusion. Hearts from transgenic mice overexpressing SNRK have decreased glucose and palmitate metabolism and oxygen consumption, but maintained power and function. They also exhibit decreased uncoupling protein 3 (UCP3) and mitochondrial uncoupling. Conversely, Snrk knockout mouse hearts have increased glucose and palmitate oxidation and UCP3. SNRK knockdown in cardiac cells decreases mitochondrial efficiency, which is abolished with UCP3 knockdown. We show that Tribbles homologue 3 (Trib3) binds to SNRK, and downregulates UCP3 through PPARα. Finally, SNRK is increased in cardiomyopathy patients, and SNRK reduces infarct size after ischaemia/reperfusion. SNRK also decreases cardiac cell death in a UCP3-dependent manner. Our results suggest that SNRK improves cardiac mitochondrial efficiency and ischaemic protection.

Does a Reduction in the Glomerular Filtration Rate Increase the Overall Severity of Coronary Artery Stenosis?

Junichi Nishida, Nobuaki Kokubu, Mina Kawamukai, Akiyoshi Hashimoto, Hirofumi Ohnishi, Hidemichi Kouzu, Yoshito Ohnuma, Tohru Hasegawa, Akihito Tsuchida, Tetsuji Miura

Internal medicine (Tokyo, Japan) ( (一社)日本内科学会 ) 55 ( 8 ) 871 - 7 2016年 [国内誌]

OBJECTIVE: Chronic kidney disease is a risk factor of coronary events, however, its impact on coronary artery stenosis has not yet been clarified with the use of a large database. We examined the association between a reduced glomerular filtration rate (GFR) and the overall severity of coronary stenosis. METHODS: We enrolled 1,150 patients [mean age, 68±12 (SD) years; 66.6% men] who consecutively underwent coronary angiography for suspected stable angina pectoris. The overall severity of stenosis in the coronary arteries was assessed by the Gensini score (GS), and its logarithmic values (log-GS) were used for statistical analyses since the GS does not follow a normal distribution. RESULTS: The log-GS was significantly larger in men than in women (2.5±1.5 vs. 1.9±1.7), while the estimated GFR (eGFR) and comorbidities were comparable between both sexes. A multivariate regression analysis indicated that age, smoking, eGFR, HDL-cholesterol and HbA1c were independent explanatory variables of the log-GS in men, although the eGFR explained only 1.2% of the log-GS variation. In women, the eGFR was not included in the significant explanatory variables shown by the multivariate analysis. However, the sex difference in the regression for the eGFR-log-GS relationship was not statistically significant. CONCLUSION: A reduced eGFR is a significant, but minor, determinant of the overall severity of coronary artery stenosis in men and potentially women.

Intervendor Variabilities of Left and Right Ventricular Myocardial Velocities among Three Tissue Doppler Echocardiography Systems

Abe, Kiyoshi, Sato, Yasumi, Yasui, Kenji, Watanabe, Naoki, Yuda, Satoshi, Kawamukai, Mina, Kouzu, Hidemichi, Muranaka, Atsuko, Hashimoto, Akiyoshi, Tsuchihashi, Kazufumi, Miura, Tetsuji, Nishi, Ryosuke, Hanada, Kyosuke, Hashimoto, Naoko

Echocardiography 32 ( 12 ) 1790 - 801 2015年12月 [国際誌]

BACKGROUND: Whether an intervendor discordance of myocardial velocities determined by tissue Doppler echocardiography (TDE) can be generalized remains unclear. We compared intervendor variabilities of left ventricular (LV) and right ventricular (RV) myocardial velocities among three TDE systems. METHODS: Examinations with TDE were performed in 41 healthy subjects and 11 patients with cardiovascular risk factors (CVR) using α-7 (V1, Hitachi Aloka Medical), Artida (V2, Toshiba Medical Systems), and Vivid E9 (V3, GE Healthcare) on the same day. Peak systolic (s'), early diastolic (e'), and late diastolic (a') myocardial velocities at medial and lateral sites of the mitral annulus and lateral site of the tricuspid annulus were measured using both pulsed-wave TDE and color TDE. Intra-observer and inter-observer variabilities were determined in 10 subjects and test-retest variability in 14 subjects. RESULTS: As for test-retest variability, reproducibilities of LV and RV myocardial velocities determined by pulsed-wave TDE and color TDE were relatively low but comparable between V1, V2, and V3. Myocardial velocities in healthy subjects determined by both pulsed-wave TDE and color TDE were significantly different among the three TDE systems. Myocardial velocities by pulsed-wave TDE in V3 were 2-12% lower (P < 0.05) than those by V2 and 5-14% lower (P < 0.05) than those by V1. Similar differences in myocardial velocities determined by both pulsed-wave TDE and color TDE were found in patients with CVR. CONCLUSIONS: LV and RV myocardial velocities determined by both pulsed-wave TDE and color TDE are vendor dependent, and reproducibility of the myocardial velocities determined by both TDE systems is relatively low.

DOI PubMed J-GLOBAL

たこつぼ心筋症におけるバルーニングパターンは臨床的背景や予後の違いを反映する:BOREAS-TCM study

NISHIDA Junichi, KOUZU Hidemichi, HASHIMOTO Akiyoshi, FUJITO Takefumi, KAWAMUKAI Mina, MOCHIZUKI Atsushi, MURANAKA Atsuko, KOKUBU Nobuaki, SHIMOSHIGE Shinya, YUDA Satoshi, HASE Mamoru, TSUCHIHASHI Kazufumi, MIURA Tetsuji

Heart and Vessels ( シュプリンガー・ジャパン(株) ) 30 ( 6 ) 789 - 97 2015年11月 [国内誌]

Whether different patterns of ventricular ballooning in takotsubo cardiomyopathy (TCM) reflect differences in trigger mechanisms or clinical outcomes is unclear. Here we examined differences in the clinical characteristics of typical and atypical forms of TCM. TCM patients (n = 251) in the BOREAS Registry were enrolled for comparison of TCM with apical ballooning (type A, n = 217) and TCM with non-apical ballooning (type non-A, n = 34). The percentage of females was significantly lower in the type non-A group (58.8 vs. 75.6 %), while other demographic parameters and triggers of TCM were similar in the two groups. Rate of mid-ventricular obstruction (MVO) was lower (2.9 vs. 14.3 %) in the type non-A group than in the type A group, though left ventricular ejection fractions in the two groups were comparable. During a follow-up period of 2.6 ± 2.8 years, TCM recurred in 2.9 % of the patients and cardiac death occurred in 4.0 %. Cox proportional hazard analysis indicated that body mass index (hazard ratio [HR]: 0.75, 95 % confidence interval [CI] 0.54-0.99) and MVO (HR: 14.71, CI 1.87-304.66) were determinants of TCM recurrence and that advanced age (HR: 1.09, CI 1.02-1.17) and cardiogenic shock (HR: 4.27, CI 1.07-18.93) were significantly associated with cardiac death. In conclusion, approximately 20 % of TCM patients show non-apical left ventricular ballooning, and female sex and MVO are less frequent in this type than in apical ballooning type TCM. Low body mass index and MVO are risk factors of recurrence, and advanced age and cardiogenic shock are risk factors of cardiac death in TCM.

DOI PubMed J-GLOBAL

Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats

Murase, Hiromichi, Kuno, Atsushi, Kuno, Atsushi, Miki, Takayuki, Tanno, Masaya, Yano, Toshiyuki, Kouzu, Hidemichi, Ishikawa, Satoko, Tobisawa, Toshiyuki, Ogasawara, Makoto, Nishizawa, Keitaro, Miura, Tetsuji

Cardiovascular Diabetology 14 ( 1 ) 103 - 103 2015年08月 [国際誌]

BACKGROUND: Type 2 diabetes mellitus (T2DM) worsens the outcome after myocardial infarction (MI). Here, we hypothesized that inhibition of dipeptidyl peptidase-4 (DPP-4) improves survival after MI in T2DM by modifying autophagy in the non-infarcted region of the heart. METHODS AND RESULTS: Under baseline conditions, there was no significant difference between levels of myocardial autophagy marker proteins in OLETF, a rat model of T2DM, and in LETO, a non-diabetic control. However, in contrast to the response in LETO, LC3-II protein and LC3-positive autophagosomes in the non-infarcted region of the myocardium were not increased after MI in OLETF. The altered autophagic response in OLETF was associated with lack of AMPK/ULK-1 activation, attenuated response of Akt/mTOR/S6 signaling and increased Beclin-1-Bcl-2 interaction after MI. Treatment with vildagliptin (10 mg/kg/day s.c.), a DPP-4 inhibitor, suppressed Beclin-1-Bcl-2 interaction and increased both LC3-II protein level and autophagosomes in the non-infarcted region in OLETF, though it did not normalize AMPK/ULK-1 or mTOR/S6 signaling. Plasma insulin level, but not glucose level, was significantly reduced by vildagliptin at the dose used in this study. Survival rate at 48 h after MI was significantly lower in OLETF than in LETO (32 vs. 82%), despite similar infarct sizes. Vildagliptin improved the survival rate in OLETF to 80%, the benefit of which was abrogated by chloroquine, an autophagy inhibitor. CONCLUSIONS: The results indicate that vildagliptin reduces T2DM-induced increase in post-MI acute mortality possibly by restoring the autophagic response through attenuation of Bcl-2-Beclin-1 interaction.

DOI PubMed J-GLOBAL

Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart

Kouzu, Hidemichi, Miki, Takayuki, Tanno, Masaya, Kuno, Atsushi, Kuno, Atsushi, Yano, Toshiyuki, Itoh, Takahito, Sato, Tatsuya, Sunaga, Daisuke, Murase, Hiromichi, Tobisawa, Toshiyuki, Ogasawara, Makoto, Ishikawa, Satoko, Miura, Tetsuji

Journal of Molecular and Cellular Cardiology 80 136 - 45 2015年03月 [国際誌]

Type 2 diabetes mellitus (T2DM) is often complicated with diastolic heart failure, which decompensates under increased afterload. Focusing on cardiac metabolomes, we examined mechanisms by which T2DM augments ventricular diastolic stiffness in response to pressure overloading. Pressure-volume relationships (PVRs) and myocardial metabolomes were determined at baseline and during elevation of aortic pressure by phenylephrine infusion in a model of T2DM, OLETF, and its non-diabetic control, LETO. Pressure overloading augmented diastolic stiffness without change in systolic reserve in OLETF as indicated by a left-upward shift of end-diastolic PVR. In contrast, PVRs under cardioplegic arrest in buffer-perfused isolated hearts were similar in OLETF and LETO, indicating that extracellular matrix or titin remodeling does not contribute to the afterload-induced increase in stiffness of the beating ventricle of OLETF. Metabolome analyses revealed impaired glycolysis and facilitation of the pentose phosphate pathway in OLETF. Pressure overloading significantly reduced ATP and total adenine nucleotides by 34% and 40%, respectively, in OLETF but not in LETO, while NADH-to-NAD(+) ratios were similar in the two groups. The decline in ATP by pressure overloading in OLETF was associated with increased inosine 5-monophosphate and decreased adenosine levels, being consistent with the 2.5-times higher activity of cardiac AMP deaminase in OLETF. Tissue ATP level was negatively correlated with tau of LV pressure and LVEDP. These results suggest that ATP depletion due to excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies ventricular stiffening during acute pressure overloading in T2DM hearts.

DOI PubMed J-GLOBAL

Translocation of glycogen synthase kinase-3β (GSK-3β), a trigger of permeability transition, is kinase activity-dependent and mediated by interaction with voltage-dependent anion channel 2 (VDAC2)

Tanno, Masaya, Kuno, Atsushi, Kuno, Atsushi, Ishikawa, Satoko, Miki, Takayuki, Kouzu, Hidemichi, Yano, Toshiyuki, Murase, Hiromichi, Tobisawa, Toshiyuki, Ogasawara, Makoto, Miura, Tetsuji, Horio, Yoshiyuki

Journal of Biological Chemistry 289 ( 42 ) 29285 - 96 2014年10月 [国際誌]

Glycogen synthase kinase-3β (GSK-3β) is a major positive regulator of the mitochondrial permeability transition pore (mPTP), a principle trigger of cell death, under the condition of oxidative stress. However, the mechanism by which cytosolic GSK-3β translocates to mitochondria, promoting mPTP opening, remains unclear. Here we addressed this issue by analyses of the effect of site-directed mutations in GSK-3β on mitochondrial translocation and protein/protein interactions upon oxidative stress. H9c2 cardiomyoblasts were transfected with GFP-tagged GSK-3β (WT), a mutant GSK-3β insensitive to inhibitory phosphorylation (S9A), or kinase-deficient GSK-3β (K85R). Time lapse observation revealed that WT and S9A translocated from the cytosol to the mitochondria more promptly than did K85R after exposure to oxidative stress. H2O2 increased the density of nine spots on two-dimensional gel electrophoresis of anti-GSK-3β-immunoprecipitates by more than 3-fold. MALDI-TOF/MS analysis revealed that one of the spots contained voltage-dependent anion channel 2 (VDAC2). Knockdown of VDAC2, but not VDAC1 or VDAC3, by siRNA attenuated both the mitochondrial translocation of GSK-3β and mPTP opening under stress conditions. The mitochondrial translocation of GSK-3β was attenuated also when Lys-15, but not Arg-4 or Arg-6, in the N-terminal domain of GSK-3β was replaced with alanine. The oxidative stress-induced mitochondrial translocation of GSK-3β was associated with an increase in cell death, which was suppressed by lithium chloride (LiCl), a GSK-3β inhibitor. These results demonstrate that GSK-3β translocates from the cytosol to mitochondria in a kinase activity- and VDAC2-dependent manner in which an N-terminal domain of GSK-3β may function as a mitochondrial targeting sequence.

DOI PubMed J-GLOBAL

Inter-vendor variability of left ventricular volumes and strains determined by three-dimensional speckle tracking echocardiography

Yuda, Satoshi, Yuda, Satoshi, Kawamukai, Mina, Kouzu, Hidemichi, Muranaka, Atsuko, Kokubu, Nobuaki, Hashimoto, Akiyoshi, Tsuchihashi, Kazufumi, Miura, Tetsuji, Watanabe, Naoki, Sato, Yasumi, Abe, Kiyoshi

Echocardiography 31 ( 5 ) 597 - 604 2014年05月 [国際誌]

BACKGROUND: Inter-vendor discordance in three-dimensional speckle-tracking echocardiography (3DS) remains uncharacterized. We aimed to examine inter-vendor discordance of left ventricular (LV) volumes, and functional parameters and their reproducibilities between two commercially available 3DS systems. METHODS: Echocardiographic examinations with 3DS were performed in 26 healthy subjects (age 34 ± 13 years, 85% men) using a Vivid E9 system (V1) with 4V probe (GE Health Care) and Artida (V2) with PST-25SX probe (Toshiba Medical Systems) on the same day. LV variables and global LV longitudinal, circumferential, radial, and area strains were measured by vendor-specific softwares, 4D strain EchoPAC BT11 (for V1) and 3D WMT (for V2), respectively. Reproducibility of data was assessed by an intra-class correlation coefficient (ICC). RESULTS: The mean time required for 3DS analysis was 5.4 ± 1.5 min for V1, being 21% less than that for V2 (6.8 ± 1.9 min, P < 0.01). Reproducibilities of all LV strains were comparable between V1 (ICC 0.50-0.82) and V2 (ICC 0.51-0.76), except for intra-observer and inter-observer reproducibilities of radial strain being lower in V2 (ICC for V1 0.82 and 0.82 and ICC for V2 0.44 and 0.40, respectively). LV strains in all directions and area were significantly different between V1 and V2, though LV volumes and ejection fraction were comparable. CONCLUSIONS: Global longitudinal, circumferential, and area LV strains are reproducible in both 3DS vendors. However, values of three-dimensional LV strains by 3DS are highly vendor-dependent.

DOI PubMed J-GLOBAL

2型糖尿病はKv4.2およびKChIP2の下方制御を伴う一過性外向きK<sup>+</sup>電流の心内膜下優勢な減少を誘発する

SATO Tatsuya, KOBAYASHI Takeshi, KUNO Atsushi, MIKI Takayuki, TANNO Masaya, KOUZU Hidemichi, ITOH Takahito, ISHIKAWA Satoko, KOJIMA Takashi, MIURA Tetsuji, TOHSE Noritsugu

American Journal of Physiology 306 ( 7 ) H1054-65 2014年04月 [国際誌]

In the present study, we examined if and how cardiac ion channels are modified by type 2 diabetes mellitus (T2DM). Subendocardial (Endo) myocytes and subepicardial (Epi) myocytes were isolated from left ventricles of Otsuka-Long-Evans-Tokushima Fatty rats (OLETF) rats, a rat model of T2DM, and Otsuka-Long-Evans-Tokushima (LETO) rats (nondiabetic control rats). Endo and Epi myocytes were used for whole cell patch-clamp recordings and for protein and mRNA analyses. Action potential durations in Endo and Epi myocytes were longer in OLETF rats than in LETO rats, and the difference was larger in Endo myocytes. Steady-state transient outward K+ current (Ito) density was reduced in Endo but not Epi myocytes of OLETF rats compared with LETO rats, although the contribution of the fast component of Ito recovery from inactivation was smaller in both Endo and Epi myocytes of OLETF rats than in LETO rats. Kv4.2 protein was reduced only in Endo myocytes in OLETF rats, although voltage-gated K+ channel-interacting protein 2 (KChIP2) protein levels in both Endo and Epi myocytes were lower in OLETF rats than in LETO rats. Corresponding regional differences in mRNA levels of KChIP2 and Kv4.2 were observed between OLETF and LETO rats. mRNA levels of Iroquois homeobox 5 in Endo myocytes were 53% higher in OLETF rats than in LETO rats. Densities of inward rectifier K+ current and L-type Ca2+ current and mRNA levels of Kv4.3 and Kv1.4 were similar in OLETF and LETO rats. In conclusion, T2DM induces Endo-predominant prolongation of the action potential duration via a reduction of the fast component of Ito recovery from inactivation and reduced steady-state Ito, in which downregulation of Kv4.2 and KChIP2 may be involved. Increased Iroquois homeobox 5 expression may underlie Kv4.2 downregulation in T2DM.

DOI PubMed J-GLOBAL

Atrial electromechanical interval may predict cardioembolic stroke in apparently low risk elderly patients with paroxysmal atrial fibrillation

Hoshi, Yoko, Sato, Shoko, Sakasai, Takuya, Oka, Makoto, Katayama, Harumi, Sato, Masaya, Nozawa, Yukinaga, Nishihara, Masahiro, Doi, Atsushi, Nishimiya, Takatoshi, Ogasawara, Makoto, Yuda, Satoshi, Yuda, Satoshi, Kouzu, Hidemichi, Miura, Tetsuji

Echocardiography 31 ( 2 ) 140 - 8 2014年02月 [国際誌]

BACKGROUND: A considerable number of patients with atrial fibrillation (AF) develop cardioembolic stroke (CE) despite low CHADS2 score. We examined the possibility that use of the atrial electromechanical interval (AEMI) improves prediction of CE in patients with paroxysmal AF (PAF), particularly those with low CHADS2 score. METHODS: We consecutively enrolled 108 patients with nonvalvular PAF and 52 healthy subjects as controls. The PAF patients were divided into 2 groups depending on presence (n = 36) or absence (n = 72) of the history of CE. Left atrial (LA) volume index (LAVI), peak myocardial velocity during late diastole (a'), and AEMI as time from onset of P-wave to onset of lateral a' were measured. RESULTS: Patients with PAF had significantly larger LAVI, longer AEMI, and lower lateral a' than those in controls. Area under the curves for LAVI, lateral a', and AEMI for identifying patients with PAF were 0.70, 0.69, and 0.88, respectively. Multivariate logistic regression analysis indicated that age, use of antiarrhythmic drugs, and AEMI, but not LAVI or a', were independently associated with history of CE in patients with PAF. PAF patients were categorized into low risk by CHADS2 score (i.e. CHADS2 score = 0 or 1, n = 60), those with prolonged AEMI (>82 msec) had significantly higher rates of CE than those with ≤ 82 msec (48% vs. 15%, P < 0.05). CONCLUSION: As compared with echocardiographic parameters of LA size and LA function, AEMI appears to be more useful for identifying PAF patients. AEMI may enable to detect high risk PAF patients, especially those categorized into low risk by CHADS2 score.

DOI PubMed J-GLOBAL

心臓の炎症性筋線維芽細胞性腫瘍 IgG4関連疾患と重複か?

KOUZU Hidemichi, MIKI Takayuki, MIZUNO Masashi, KIMURA Yukishige, MURANAKA Atsuko, YUDA Satoshi, YUDA Satoshi, KEIRA Yoshiko, HASEGAWA Tadashi, MIYAKI Yasuko, TAKAGI Nobuyuki, HIGAMI Tetsuya, MIURA Tetsuji

Circulation Journal ( (一社)日本循環器学会 ) 78 ( 4 ) 1006 - 8 2014年 [国内誌]

PubMed J-GLOBAL

Diabetic cardiomyopathy: Pathophysiology and clinical features

Miki, Takayuki, Yuda, Satoshi, Kouzu, Hidemichi, Miura, Tetsuji

Heart Failure Reviews 18 ( 2 ) 149 - 66 2013年03月 [国際誌]

Since diabetic cardiomyopathy was first reported four decades ago, substantial information on its pathogenesis and clinical features has accumulated. In the heart, diabetes enhances fatty acid metabolism, suppresses glucose oxidation, and modifies intracellular signaling, leading to impairments in multiple steps of excitation-contraction coupling, inefficient energy production, and increased susceptibility to ischemia/reperfusion injury. Loss of normal microvessels and remodeling of the extracellular matrix are also involved in contractile dysfunction of diabetic hearts. Use of sensitive echocardiographic techniques (tissue Doppler imaging and strain rate imaging) and magnetic resonance spectroscopy enables detection of diabetic cardiomyopathy at an early stage, and a combination of the modalities allows differentiation of this type of cardiomyopathy from other organic heart diseases. Circumstantial evidence to date indicates that diabetic cardiomyopathy is a common but frequently unrecognized pathological process in asymptomatic diabetic patients. However, a strategy for prevention or treatment of diabetic cardiomyopathy to improve its prognosis has not yet been established. Here, we review both basic and clinical studies on diabetic cardiomyopathy and summarize problems remaining to be solved for improving management of this type of cardiomyopathy.

DOI PubMed J-GLOBAL

Assessment of left atrial deformation and synchrony by three-dimensional speckle-tracking echocardiography: Comparative studies in healthy subjects and patients with atrial fibrillation

Mochizuki, Atsushi, Yuda, Satoshi, Yuda, Satoshi, Kawamukai, Mina, Nishida, Junichi, Kouzu, Hidemichi, Muranaka, Atsuko, Kokubu, Nobuaki, Shimoshige, Shinya, Hashimoto, Akiyoshi, Tsuchihashi, Kazufumi, Miura, Tetsuji, Watanabe, Naoki, Oi, Yukiko

Journal of the American Society of Echocardiography 26 ( 2 ) 165 - 74 2013年02月 [国際誌]

BACKGROUND: The aim of this study was to examine whether left atrial (LA) strain and synchrony can be assessed using three-dimensional (3D) speckle-tracking echocardiography (STE) and how 3D STE parameters are modified by atrial fibrillation (AF). METHODS: LA peak ventricular systolic longitudinal strain (LSs), circumferential strain (CSs), and area strain (ASs) and LA peak pre-atrial contraction longitudinal strain, circumferential strain (CSa), and area strain were determined using 3D STE, and SDs of times to peaks of regional LA strain were calculated as indices of LA dyssynchrony. Three-dimensional speckle-tracking was able to measure LA strain in 75 of the 77 healthy subjects and in all 47 patients with AF (31 with paroxysmal AF [PAF] and 16 with permanent AF). RESULTS: The mean time for analysis with 3D STE was 18% shorter than with two-dimensional (2D) STE (P < .05). On 3D STE, values of interobserver and intraobserver variability of LA strain were <10% and <12%, respectively. LSs, CSs, ASs, and 2D STE LSs were reduced in patients with PAF compared with controls, and further reductions of these parameters were observed in patients with permanent AF. SDs of LSs, CSs, and ASs were similarly larger in patients with PAF and in those with permanent AF compared with controls. Patients with PAF showed smaller LA peak pre-atrial contraction longitudinal strain, CSa, and LA peak pre-atrial contraction area strain and larger SDs of CSa and LA peak pre-atrial contraction area strain compared with controls. In multivariate analysis, 2D STE LSs (P = .044), LSs (P = .040), ASs (P = .007), and CSa (P = .020) were independent predictors of PAF. CONCLUSIONS: Three-dimensional speckle-tracking enables the measurement of both LA strain and synchrony with excellent reproducibility. Three-dimensional LA strain appears to be beneficial compared with 2D LA strain for identifying patients with PAF.

DOI PubMed J-GLOBAL

追跡調査23年間の劇症1型糖尿病における膵臓病理組織:症例報告

SATO Tatsuya, MIKI Takayuki, MURAKAMI Naoto, HIROHASHI Yoshihiko, KOUZU Hidemichi, FURUHASHI Masato, TANNO Masaya, YUDA Satoshi, SAITOH Shigeyuki, HASEGAWA Tadashi, MIURA Tetsuji

Pathology International ( John Wiley & Sons Australia, Ltd ) 62 ( 12 ) 827 - 9 2012年12月 [国際誌]

DOI PubMed J-GLOBAL

2型糖尿病ゴトー-カキザキラット心臓において損なわれるミトコンドリア膜透過性遷移孔の細胞保護的調節

ITOH Takahito, KOUZU Hidemichi, MIKI Takayuki, TANNO Masaya, KUNO Atsushi, SATO Tatsuya, SUNAGA Daisuke, MURASE Hiromichi, MIURA Tetsuji

Journal of Molecular and Cellular Cardiology 53 ( 6 ) 870 - 9 2012年12月 [国際誌]

Our recent studies indicated that up-regulation of calcineurin activity and unfolded protein responses (UPRs) disrupt cytoprotective Akt- and ERK-signaling in OLETF, a model of obese type 2 diabetes (T2DM). To determine whether the mechanisms can be generalized, we used Goto-Kakizaki rats (GK), a model of non-obese T2DM, in this study. Infarct sizes after 20-min ischemia/2-h reperfusion were similar in GK and non-diabetic controls, Wistar rats (Wistar). However, erythropoietin (EPO) limited infarct size in Wistar (64.0±5.3% vs. 45.7±4.4%, p<0.05) but not in GK (56.2±2.2% vs. 52.6±2.3%). Levels of calcineurin activity and EPO-induced phosphorylation of Akt and ERK were similar in GK and Wistar, though cytosolic HSP70 level was 50% lower and mitochondrial HSP60 level was 60% higher in GK. EPO preserved mitochondrial calcium retention capacity (CRC), an index of the threshold for opening of the mitochondrial permeability transition pore (mPTP), after ischemia/reperfusion in Wistar but not in GK. Interaction of cyclophilin D (CypD) with mitochondrial inorganic phosphate carrier (PiC), which sensitizes the mPTP, was enhanced in GK. There was a negative exponential relationship between CypD-PiC interaction and CRC upon reperfusion, indicating that increase in CRC by reduction of CypD-PiC interaction is smaller when CypD-PiC interaction level is at a higher range. A chemical chaperone, 4-phenylbutyric acid, attenuated the changes in HSPs and CypD-PiC interaction and restored responses of CRC and infarct size to EPO in GK. These results suggest that cytoprotective regulation of the mPTP is impaired in GK by enhanced CypD-PiC interaction in which UPRs are involved.

DOI PubMed J-GLOBAL

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