研究者詳細 - 丹野　雅也

Misc - 丹野　雅也

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Diverse mechanisms are responsible for myocardial p38-MAPK activation in response to ischemia and tumour necrosis factor

M Tanno, R Bassi, A Saurin, M Marber

HEART ( B M J PUBLISHING GROUP ) 89 A14 - A14 2003年05月

研究発表ペーパー・要旨（国際会議）

Infarct size limitation by nicorandil: Roles of mitochondrial K-ATP channels, sarcolemmal K-ATP channels, and protein kinase C

A Tsuchida, T Miura, M Tanno, J Sakamoto, T Miki, A Kuno, T Matsumoto, Y Ohnuma, Y Ichikawa, K Shimamoto

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY ( ELSEVIER SCIENCE INC ) 40 ( 8 ) 1523 - 1530 2002年10月

OBJECTIVES This study aimed to examine: 1) whether nicorandil protects the ischemic myocardium by activating sarcolemmal adenosine triphosphate (ATP)-sensitive K+ (sarcK(ATP)) channels or the mitochondrial K-ATP (mitoK(ATP)) channels, and 2) whether protein kinase C (PKC) activity is necessary for cardioprotection afforded by nicorandil. BACKGROUND Nicorandil is a hybrid of nitrate and a K-ATP channel opener that activates the sarcK(ATP) and mitoK(ATP) channels. Both of these K-ATP channels are regulated by PKC, and this kinase may be activated by nitric oxide and also by oxygen free radicals (OFR) generated after mitoK(ATP) channel opening. METHODS In isolated rabbit hearts, infarction was induced by 30-min global ischemia/2-h reperfusion with monitoring of the activation recovery interval (ARI), an index of action potential duration. Protein kinase C translocation was assessed by Western blotting. RESULTS Nicorandil did not change ARI before ischemia, but it accelerated ARI shortening after the onset of ischemia and reduced infarct size by 90%. A sarcK(ATP) channel selective blocker, HMR1098, abolished acceleration of ischemia-induced ARI-shortening by nicorandil and eliminated 40% of nicorandil-induced infarct size limitation. A mitoK(ATP) channel selective blocker, 5-hydroxydecanoate, abolished the protection afforded by nicorandil without affecting ARI. Cardioprotection by nicorandil was inhibited neither by an OFR scavenger, N-2-mercaptopropionylglycine nor by a PKC inhibitor, calphostin C, at a dose that was capable of inhibiting PKC-epsilon translocation after preconditioning. CONCLUSIONS Both the sarcK(ATP) and mitoK(ATP) channels are involved in anti-infarct tolerance afforded by nicorandil, but PKC activation induced by nitric oxide or OFR generation, if any, does not play a crucial role. (C) 2002 by the American College of Cardiology Foundation.

DOI

The role of mitochondrial KATP-channels in preconditioning in the Langendorff-perfused mouse heart - trigger or mediator?

AMN Kabir, M Tanno, DA Gorog, MJ Shattock, MS Marber

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY ( BLACKWELL PUBLISHING ASIA ) 29 ( 8 ) A87 - A88 2002年08月

研究発表ペーパー・要旨（国際会議）

Opening of mitochondrial K-ATP channel occurs downstream of PKC-epsilon activation in the mechanism of preconditioning

Y Ohnuma, T Miura, T Miki, M Tanno, A Kuno, A Tsuchida, K Shimamoto

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY ( AMER PHYSIOLOGICAL SOC ) 283 ( 1 ) H440 - H447 2002年07月

We examined whether the mitochondrial ATP-sensitive K channel (K-ATP) is an effector downstream of protein kinase C-epsilon (PKC-epsilon) in the mechanism of preconditioning (PC) in isolated rabbit hearts. PC with two cycles of 5-min ischemia/5-min reperfusion before 30-min global ischemia reduced infarction from 50.3 +/- 6.8% of the left ventricle to 20.3 +/- 3.7%. PC significantly increased PKC-epsilon protein in the particulate fraction from 51 +/- 4% of the total to 60 +/- 4%, whereas no translocation was observed for PKC-delta and PKC-alpha. In mitochondria separated from the other particulate fractions, PC increased the PKC-epsilon level by 50%. Infusion of 5-hydroxydecanoate (5-HD), a mitochondrial K-ATP blocker, after PC abolished the cardioprotection of PC, whereas PKC-epsilon translocation by PC was not interfered with 5-HD. Diazoxide, a mitochondrial K-ATP opener, infused 10 min before ischemia limited infarct size to 5.2 +/- 1.4%, but this agent neither translocated PKC-epsilon by itself nor accelerated PKC-epsilon translocation after ischemia. Together with the results of earlier studies showing mitochondrial K-ATP opening by PKC, the present results suggest that mitochondrial K-ATP-mediated cardioprotection occurs subsequent to PKC-epsilon activation by PC.

DOI

Opening of the mitochondrial K-ATP channel is downstream of protein kinase C-epsilon activation in the cardioprotective mechanism of ischemic preconditioning

Y Ohnuma, T Miki, M Tanno, S Genda, A Kuno, T Miura

CIRCULATION ( LIPPINCOTT WILLIAMS & WILKINS ) 104 ( 17 ) 16 - 16 2001年10月

研究発表ペーパー・要旨（国際会議）

Roles of microtubules and actin filaments in the mechanism of ischemic preconditioning

T Miura, T Miki, Y Ohnuma, M Tanno, K Shimamoto

CIRCULATION ( LIPPINCOTT WILLIAMS & WILKINS ) 104 ( 17 ) 60 - 60 2001年10月

研究発表ペーパー・要旨（国際会議）

Blockade of gap junction communication during the early period of ischemia protects cardiomyocytes from infarction

M Tanno, A Tsuchida, Y Nishino, T Matsumoto, S Genda, J Sakamoto, T Miura

CIRCULATION ( LIPPINCOTT WILLIAMS & WILKINS ) 104 ( 17 ) 43 - 43 2001年10月

研究発表ペーパー・要旨（国際会議）

Failure of adenosine receptors to activate PKC-epsilon is responsible for loss of cardioprotection of preconditioning in the myocardium undergoing post-infarct remodeling

T Miki, T Miura, A Tsuchida, J Sakamoto, M Tanno, A Kuno, Y Nishino, K Shimamoto

CIRCULATION ( LIPPINCOTT WILLIAMS & WILKINS ) 104 ( 17 ) 209 - 209 2001年10月

研究発表ペーパー・要旨（国際会議）

Contribution of both the sarcolemmal K-ATP and mitochondrial K-ATP channels to infarct size limitation by K-ATP channel openers: differences from preconditioning in the role of sarcolemmal K-ATP channels

M Tanno, T Miura, A Tsuchida, T Miki, Y Nishino, Y Ohnuma, K Shimamoto

NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY ( SPRINGER-VERLAG ) 364 ( 3 ) 226 - 232 2001年09月

DOI PubMed CiNii

Critical timing of mitochondrial K(ATP) channel opening for enhancement of myocardial tolerance against infarction

A Tsuchida, T Miura, T Miki, A Kuno, M Tanno, Y Nozawa, S Genda, T Matsumoto, K Shimamoto

BASIC RESEARCH IN CARDIOLOGY ( SPRINGER HEIDELBERG ) 96 ( 5 ) 446 - 453 2001年09月

Objective The present study was designed to assess the relationship between the timing of a mitoK(ATP) channel opener, diazoxide, and its infarct size-limiting effect. Methods In isolated rabbit hearts, infarction was induced by 30 min of global ischemia and 2 h of reperfusion, and infarct size was determined by tetrazolium staining and expressed as a percentage of the left ventricle (%IS/LV). Diazoxide, a mitoKATP channel selective opener, and/or 5-hydroxydecanoate (5-HD), a mitoK(ATP) channel blocker, were infused before or after the onset of ischemia. When these agents were infused during the ischemic period, they were dissolved in a hypoxic buffer at concentrations 10-fold higher than those in the pre-ischemic period, and the infusion rate was set at 2 % of the pre-ischemic coronary flow. Results in untreated controls, %IS/LV was 53.2 +/- 4.1 (SE). Pretreatment with diazoxide (100 muM) with a 10-min washout period reduced %IS/LV to 7.8 +/- 2.4 and this protection was abolished by co-infusion of 5-HD (50 muM). Pre-ischemic infusion of diazoxide without a washout period reduced %IS/LV to 7.3 +/- 1.4, and infusion of diazoxide from 10 min after the onset of ischemia also limited %IS/LV to 14.9 +/- 4.6. However, diazoxide infusion from 25 min after the onset of ischemia failed to reduce infarct size (%IS/LV = 54.5 +/- 7.2). Furthermore, pretreatment with 5-HD (50 muM) also completely abolished the protection afforded by early post-ischemic diazoxide infusion (%IS/LV = 48.3 +/- 6.5). Neither infusion of 5-HD nor the anoxic vehicle alone during ischemia modified %IS/LV. Conclusion These findings suggest that opening of mitoKATP channels before ischemia and during early ischemia, but not that upon reperfusion, is important for enhancement of myocardial tolerance against infarction.

DOI

Opening of the mitochondrial KATP channel occurs downstream of protein kinase C in the cardioprotective mechanism of ischaemic preconditioning

T Miki, T Miura, Y Ohnuma, M Tanno, A Kuno, T Matsumoto, K Shimamoto

EUROPEAN HEART JOURNAL ( W B SAUNDERS CO LTD ) 22 669 - 669 2001年09月

研究発表ペーパー・要旨（国際会議）

Infarct size limitation by bradykinin receptor activation is mediated by the mitochondrial but not by the sarcolemmal KATP channel

H Kita, T Miura, T Miki, S Genda, M Tanno, T Fukuma, K Shimamoto

CARDIOVASCULAR DRUGS AND THERAPY ( KLUWER ACADEMIC PUBL ) 14 ( 5 ) 497 - 502 2000年09月

Earlier studies have shown that activation of bradykinin B-2 receptor triggers protein kinase C (PKC)-mediated cardioprotective mechanism in ischemic preconditioning (PC). In the present study, we examined whether the effector in this B-2-receptor triggered pathway of PC is the ATP sensitive potassium (K-ATP) channel in the mitochondria (mito-K-ATP channel) or K-ATP channel in the sarcolemma (sarc-K-ATP channel). Isolated rabbit hearts were perfused with modified Krebs-Henseleit buffer in a Langendorff mode, and regional myocardial ischemia was induced by occluding a left coronary artery for 30 min and then reperfusing for 2 hours. Infarct size was determined by triphenyltetrazolium chloride staining and expressed as a percentage of area at risk (% IS/AR). Infusion of bradykinin (500 nmol/L) for 15 min prior to ischemia significantly reduced % IS/AR from 37.4 +/- 2.9 (SE) of the untreated controls to 12.0 +/- 3.3%. This protective effect of bradykinin was completely abolished by coinfusion of 5-hydroxydecanoate (5-HD, 50 mu mol/L), a selective mito-K-ATP channel blocker (% IS/AR = 44.2 +/- 6.4). In contrast, a high dose of HMR1098 (20 mu mol/L), which is a newly developed sarc-K-ATP channel selective blocker with IC50 of 0.6 mu mol/L, failed to modify the infarct size limitation by preischemic infusion of bradykinin (% IS/AR = 11.7 +/- 3.4). Neither 5-HD nor HMR1098 alone modified infarct size (% IS/AR = 37.8 +/- 3.8 and 35.1 +/- 6.2, respectively). These results suggest that opening of the mito-K-ATP channel but not the sarc-K-ATP channel is involved in infarct size limitation by a mechanism triggered by bradykinin B-2 receptor activation.

DOI

Subtypes of ATP-sensitive potassium channels (KATP) affording anti-infarct tolerance in the heart: mitochondrial KATP versus sarcolemmal KATP

M Tanno, T Miura, A Kuno, T Miki, A Tsuchida, K Shimamoto

EUROPEAN HEART JOURNAL ( W B SAUNDERS CO LTD ) 21 669 - 669 2000年08月

研究発表ペーパー・要旨（国際会議）

コロキウムVII-1 Preconditioning効果 : 基礎の立場から

三浦哲嗣, 土田哲人, 三木隆幸, 丹野雅也, 野沢幸永, 現田聡, 島本和明

Japanese circulation journal ( 社団法人日本循環器学会 ) 64 94 - 94 2000年03月

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P268 Bradykinin受容体を介したpreconditioning機構にはmitochondrial K^<ATP> channelsが寄与する

北宏之, 三浦哲嗣, 土田哲人, 三木隆幸, 福真隆行, 丹野雅也, 野沢幸永, 松本倫明, 島本和明

Japanese circulation journal ( 社団法人日本循環器学会 ) 64 526 - 526 2000年03月

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Roles of tyrosine kinase and protein kinase C in infarct size limitation by repetitive ischemic preconditioning in the rat

M Tanno, A Tsuchida, Y Nozawa, T Matsumoto, T Hasegawa, T Miura, K Shimamoto

JOURNAL OF CARDIOVASCULAR PHARMACOLOGY ( LIPPINCOTT WILLIAMS & WILKINS ) 35 ( 3 ) 345 - 352 2000年03月

In this study, we examined the possibility that infarct-size limitation by repetitive preconditioning (PC) is achieved by activation of both protein kinase C (PKC) and tyrosine kinase. In addition, we assessed whether such kinase activation is triggered by angiotensin II type 1 (AT(1)) and alpha(1)-adrenergic receptors and whether sarcolemmal and mitochondrial adenosine triphosphate (ATP)-sensitive potassium (K-ATP) channels play roles as effecters of cardioprotection in the rat. Under pentobarbital anesthesia, myocardial infarction was induced by 20-min coronary occlusion and 3-h reperfusion in the rat. Infarct size was determined by tetrazolium and expressed as a percentage of area at risk (%IS/AR). PC with one cycle of 5-min ischemia/5-min reperfusion before 20-min ischemia significantly reduced %IS/AR from the control value of 49.4 +/- 2.0 to 35.4 +/- 2.8, and repetitive PC with two cycles of 5-min ischemia/5-min reperfusion further limited %IS/AR to 3.2 +/- 0.9. Infarct-size limitation by single-cycle PC was completely abolished by a PKC inhibitor, staurosporine (100 mu g/kg; %IS/ AR, 45.7 +/- 5.0). In contrast, the cardioprotection by repetitive PC was only partially blocked by staurosporine (%IS/AR, 19.8 +/- 2.4), another PKC inhibitor, polymyxin B (5 mg/kg; %IS/AR, 16.2 +/- 3.1), or a tyrosine kinase inhibitor, genistein (5 mg/kg; %IS/AR, 21.8 +/- 1.4). However, a combined injection of genistein and staurosporine additively inhibited protection of repetitive PC (%IS/AR, 36.4 +/- 1.7). Staurosporine, polymyxin B, or genistein alone did not modify %IS/AR in nonpreconditioned rat hearts. Infarct-size limitation by repetitive PC was not attenuated by pretreatment with a selective AT(1)-receptor blocker (CV11974, 10 mg/kg), prazosin (0.6 mg/kg; %IS/AR, 6.4 +/- 3.2 and 1.6 +/- 0.5, respectively). A selective blocker of mitochondrial K-ATP channels, 5-hydroxydecanoate (3 mg/kg), completely abolished the cardioprotective effect (%IS/AR, 50.8 +/- 3.5), but HMR1883 (3 mg/kg), a selective blocker of sarcolemmal K-ATP channels, failed to inhibit the preconditioning effect (%IS/AR, 4.4 +/- 0.7). These findings suggest that repetition of PC provokes activation of both PKC and tyrosine kinase, leading to enhanced antiinfarct tolerance by opening of mitochondrial but not sarcolemmal K-ATP channels. It is unlikely that activation of either AT(1) or alpha(1)-adrenergic receptor alone is crucial to trigger preconditioning.

DOI PubMed CiNii

Critical timing of mitochondrial K-ATP channel opening for enhancement of myocardial tolerance against infarction

A Tsuchida, A Kuno, M Tanno, Y Nozawa, T Miura

CIRCULATION ( LIPPINCOTT WILLIAMS & WILKINS ) 100 ( 18 ) 631 - 631 1999年11月

研究発表ペーパー・要旨（国際会議）

0389 プレコンディショニングの反復による梗塞抑制効果の増強におけるtyrosine kinaseとprotein kinase Cの関与

丹野雅也, 土田哲人, 三浦哲嗣, 野沢幸永, 長谷川徹, 島本和明

Japanese circulation journal ( 社団法人日本循環器学会 ) 63 ( 1 ) 245 - 245 1999年03月

CiNii

Both tyrosine kinase and protein kinase C (PKC) are involved in infarct size limitation by repetitive preconditioning (PC) in the rat

M Tanno, A Tsuchida, T Miura, T Hasegawa, K Shimamota

CIRCULATION ( LIPPINCOTT WILLIAMS & WILKINS ) 98 ( 17 ) 71 - 71 1998年10月