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Papers by Ken Shinmura

Journal of Clinical Investigation, 2009

Lipocalin-type prostaglandin D synthase (L-PGDS), which was originally identified as an enzyme re... more Lipocalin-type prostaglandin D synthase (L-PGDS), which was originally identified as an enzyme responsible for PGD2 biosynthesis in the brain, is highly expressed in the myocardium, including in cardiomyocytes. However, the factors that control expression of the gene encoding L-PGDS and the pathophysiologic role of L-PGDS in cardiomyocytes are poorly understood. In the present study, we demonstrate that glucocorticoids, which act as repressors of prostaglandin biosynthesis in most cell types, upregulated the expression of L-PGDS together with cytosolic calcium-dependent phospholipase A2 and COX2 via the glucocorticoid receptor (GR) in rat cardiomyocytes. Accordingly, PGD2 was the most prominently induced prostaglandin in vivo in mouse hearts and in vitro in cultured rat cardiomyocytes after exposure to GR-selective agonists. In isolated Langendorff-perfused mouse hearts, dexamethasone alleviated ischemia/reperfusion injury. This cardioprotective effect was completely abrogated by either pharmacologic inhibition of COX2 or disruption of the gene encoding L-PGDS. In in vivo ischemia/reperfusion experiments, dexamethasone reduced infarct size in wild-type mice. This cardioprotective effect of dexamethasone was markedly reduced in L-PGDS-deficient mice. In cultured rat cardiomyocytes, PGD2 protected against cell death induced by anoxia/reoxygenation via the D-type prostanoid receptor and the ERK1/2-mediated pathway. Taken together, these results suggest what we believe to be a novel interaction between glucocorticoid-GR signaling and the cardiomyocyte survival pathway mediated by the arachidonic acid cascade.

Cardiovascular research, Jan 8, 2015

We investigated whether neural crest-derived cardiac resident cells contribute to the restoration... more We investigated whether neural crest-derived cardiac resident cells contribute to the restoration of intrinsic adrenergic function following transplantation in mice. Transplanted heart shows partial restoration of cardiac adrenergic activity with time. Both the intrinsic cardiac adrenergic system and extrinsic sympathetic re-innervation contribute to neuronal remodelling in the transplanted heart. Little is known about the origin and function of the intrinsic system in the transplanted heart. Heart from the protein 0-Cre/Floxed-Enhanced Green Fluorescent Protein double-transgenic mouse was transplanted onto the abdominal aorta of the non-obese diabetic/severe combined immunodeficient mouse to trace the fate of cardiac resident neural crest-derived cells. Sympathetic nerve fibres, which are predominantly localized to the epicardial surface of the heart, disappeared in the transplanted heart. Intramyocardial neural crest cells increased immediately, while neural crest-derived nucleate...

Opioids confer biphasic (early and late) cardioprotection against myocardial infarction by openin... more Opioids confer biphasic (early and late) cardioprotection against myocardial infarction by opening mitochondrial K ATP channels. It is unknown whether cyclooxygenase-2 (COX-2), which mediates ischemia-induced late preconditioning, also mediates opioidinduced cardioprotection. Isolated perfused rat hearts were subjected to 20 min of global ischemia followed by 20 min of reperfusion. BW373U86 (BW), a δ-opioid receptor agonist, was administered 1, 12, or 24 h before sacrifice. The recovery of left ventricular developed pressure (LVDP) after ischemia/reperfusion improved when BW was administered 1 or 24 h before ischemia (control: 57±8, BW 1 h: 75±5, BW 24 h: 85±6%) but not when it was administered 12 h before (60±5%). The levels of 6-keto-PGF 1α (a stable metabolite of PGI 2 ) in coronary effluent after 20 min of reperfusion were higher with 24-h BW pretreatment than in controls (1053±92 vs. 724±81 pg/mL), whereas 6-keto-PGF 1α  levels at baseline  did not differ. Administration of a selective COX-2 inhibitor, NS-398, abolished the late phase of cardioprotection (recovery of LVDP, 53±8%) and attenuated the increase in PGI 2 (706±138 pg/mL) but did not block the early phase of cardioprotection. The selective COX-1 inhibitor, SC-560, did not affect either phase of protection. Western immunoblotting revealed upregulation of PGI 2 synthase protein 24 h after BW administration without changes in COX-1 and COX-2 protein levels. In conclusion, the late (but not the early) phase of δ-opioid receptor-induced preconditioning is mediated by COX-2. A functional coupling between COX-2 and upregulated PGI 2 synthase appears to underlie this cardioprotective phenomenon in the rat.

Circulation, Oct 28, 2008

Japanese Circulation Journal, Jun 20, 1995

Japanese Heart Journal, Oct 1, 2000

ABSTRACT

Ischemic tolerance decreases with ageing and the cardioprotective effect of ischemic precondition... more Ischemic tolerance decreases with ageing and the cardioprotective effect of ischemic preconditioning (IPC) is impaired in middle-aged animals. We have demonstrated that shortterm caloric restriction (CR) improves myocardial ischemic tolerance in young and old animals via the activation of adiponectin-AMP activated kinase (AMPK)-mediated signaling.

The American journal of physiology

Nitric oxide donors attenuate myocardial stunning in conscious rabbits. Am. J. Physiol. 277 (Hear... more Nitric oxide donors attenuate myocardial stunning in conscious rabbits. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2495-H2503, 1999.-Although previous studies suggested that the protection of late preconditioning (PC) against myocardial stunning is mediated by nitric oxide (NO), direct evidence that exogenous administration of NO attenuates myocardial stunning is lacking. Furthermore, although exogenous NO administration was shown to elicit a late PC phase, it is unknown whether NO donors also induce an early PC phase. Therefore, conscious rabbits underwent two experimental stages (3 days of six 4-min occlusion/4-min reperfusion cycles each) 2 wk apart. In study I, both stages were control stages (n ϭ 7). In studies II and III, stage I was the control stage. On day 1 of stage II, seven rabbits received infusion of nitroglycerin (NTG; 2 µg·kg Ϫ1 ·min Ϫ1 iv) during the ischemia-reperfusion sequence, starting 30 min before the 1st occlusion and ending 10 min after the 6th reperfusion (study II). Another seven rabbits received infusion of NTG (2 µg · kg Ϫ1 ·min Ϫ1 iv) for 1 h followed by a 30-min washout interval and then underwent six 4-min occlusion/4-min reperfusion cycles (study III). In the control stage of all three studies, recovery of wall thickening (WTh) after occlusion/reperfusion cycles was markedly enhanced on days 2 and 3 compared with day 1, indicating late PC. In study II, infusion of NTG during the occlusion/reperfusion cycles on day 1 resulted in significant and sustained enhancement in WTh recovery. A similar attenuation of stunning was observed in study IV in six rabbits given intravenous infusion of S-nitroso-N-acetylpenicillamine (SNAP) during occlusion/ reperfusion cycles. The magnitude of the protection afforded by NTG and SNAP was comparable to that afforded by the late ischemic PC phase. In contrast, in study III infusion of NTG before occlusion/reperfusion cycles did not enhance WTh recovery, indicating that NTG failed to induce an early PC effect against stunning. This study demonstrates that administration of hemodynamically inactive doses of two unrelated NO donors alleviates myocardial stunning in conscious rabbits, providing direct evidence for a protective action of NO in this setting.

The American journal of physiology, 1999

Although previous studies suggested that the protection of late preconditioning (PC) against myoc... more Although previous studies suggested that the protection of late preconditioning (PC) against myocardial stunning is mediated by nitric oxide (NO), direct evidence that exogenous administration of NO attenuates myocardial stunning is lacking. Furthermore, although exogenous NO administration was shown to elicit a late PC phase, it is unknown whether NO donors also induce an early PC phase. Therefore, conscious rabbits underwent two experimental stages (3 days of six 4-min occlusion/4-min reperfusion cycles each) 2 wk apart. In study I, both stages were control stages (n = 7). In studies II and III, stage I was the control stage. On day 1 of stage II, seven rabbits received infusion of nitroglycerin (NTG; 2 microg. kg(-1). min(-1) iv) during the ischemia-reperfusion sequence, starting 30 min before the 1st occlusion and ending 10 min after the 6th reperfusion (study II). Another seven rabbits received infusion of NTG (2 microg. kg(-1). min(-1) iv) for 1 h followed by a 30-min washout ...

American journal of physiology. Heart and circulatory physiology, 2002

Although activation of delta-opioid receptors is known to induce both early and late precondition... more Although activation of delta-opioid receptors is known to induce both early and late preconditioning (PC) against myocardial infarction, the mechanisms for this salubrious effect are unclear. Furthermore, it is unknown whether delta-opioid receptors can also induce late PC against myocardial stunning. By using conscious rabbits (n = 120) in this study, we found that the delta-opioid receptor agonist (+/-)-4-[(alpha-R*)-alpha-[(2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,N-diethylbenzamide (BW-373U86) induced late PC against myocardial stunning 24 h after treatment and that this effect was abolished by the selective cyclooxygenase-2 (COX-2) inhibitors N-[2-(cyclohexyloxy)4-nitrophenyl]methanesulfonamide (NS-398) and celecoxib. This protective effect was also abrogated by the selective delta(1)-opioid receptor antagonist 7-benzylidenenaltrexone, indicating that the delta(1)-opioid receptor is necessary for BW-373U86-induced late PC. BW-373U86 did not induce early P...

American journal of physiology. Heart and circulatory physiology, 2002

American journal of physiology. Heart and circulatory physiology, 2003

Although protein tyrosine kinases (PTKs) signaling has been implicated in the late phase of ische... more Although protein tyrosine kinases (PTKs) signaling has been implicated in the late phase of ischemic preconditioning (PC), it is unknown whether PTK signaling is necessary for the development of nitric oxide (NO) donor-induced late PC. Thus conscious rabbits underwent a sequence of six 4-min coronary occlusion (O)/4-min reperfusion (R) cycles followed by a 5-h recovery period of reperfusion for 3 consecutive days (days 1, 2, and 3). On day 0 (24 h before the 6 O/R cycles on day 1), rabbits received no treatment (control), the NO donor diethylenetriamine (DETA)/NO (DETA/NO), the PTK inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), or DETA/NO plus PP2 (DETA/NO + PP2). In control rabbits (n = 6), the six O/R cycles on day 1 resulted in delayed functional recovery, indicating severe myocardial stunning. In rabbits pretreated with DETA/NO (n = 5) on day 1, myocardial stunning caused by the six O/R cycles on day 1 was markedly attenuated, with a significant...

Circulation research, Jan 9, 2002

Aldose reductase (AR), a member of the aldo-keto reductase superfamily, has been shown to metabol... more Aldose reductase (AR), a member of the aldo-keto reductase superfamily, has been shown to metabolize toxic aldehydes generated by lipid peroxidation, suggesting that it may serve as an antioxidant defense. To investigate its role in the late phase of ischemic preconditioning (PC), conscious rabbits underwent 6 cycles of 4-minute coronary occlusion/4-minute reperfusion. Twenty-four hours later, there was a marked increase in AR protein and activity and in the myocardial content of sorbitol, a unique product of AR catalysis. Pretreatment with N(omega)-nitro-L-arginine, a nitric oxide synthase inhibitor, or chelerythrine, a protein kinase C inhibitor (both given at doses that block late PC in this model), prevented the increase in AR protein 24 hours later, demonstrating that ischemic PC upregulates AR via nitric oxide- and protein kinase C-dependent signaling pathways. The AR-selective inhibitors tolrestat and sorbinil prevented AR-mediated accumulation of sorbitol and abrogated the i...

sensitivity in obese mice L-4F treatment reduces adiposity, increases adiponectin levels, and imp... more sensitivity in obese mice L-4F treatment reduces adiposity, increases adiponectin levels, and improves insulin [PDF] [Full Text] [Abstract] , April 1, 2009; 296 (4): E829-E841. Am J Physiol Endocrinol Metab J. F. Ndisang and A. Jadhav streptozotocin-induced diabetes Heme oxygenase system enhances insulin sensitivity and glucose metabolism in [PDF] [Full Text] [Abstract] , May 1, 2009; 296 (5): E1029-E1041. Am J Physiol Endocrinol Metab J. F. Ndisang, N. Lane and A. Jadhav hyperglycemia in type 2 diabetes Upregulation of the heme oxygenase system ameliorates postprandial and fasting [PDF] [Full Text] [Abstract] , July 1, 2009; 50 (7): 1293-1304. J. Lipid Res.

Proceedings of the National Academy of Sciences, 2000

We examined the role of cyclooxygenase-2 (COX-2) in the late phase of ischemic preconditioning (P... more We examined the role of cyclooxygenase-2 (COX-2) in the late phase of ischemic preconditioning (PC). A total of 176 conscious rabbits were used. Ischemic PC (six cycles of 4-min coronary occlusions͞4-min reperfusions) resulted in a rapid increase in myocardial COX-2 mRNA levels (؉231 ؎ 64% at 1 h; RNase protection assay) followed 24 h later by an increase in COX-2 protein expression (؉216 ؎ 79%; Western blotting) and in the myocardial content of prostaglandin (PG)E2 and 6-keto-PGF1␣ (؉250 ؎ 85% and ؉259 ؎ 107%, respectively; enzyme immunoassay). Administration of two unrelated COX-2 selective inhibitors (NS-398 and celecoxib) 24 h after ischemic PC abolished the ischemic PC-induced increase in tissue levels of PGE2 and 6-keto-PGF1␣. The same doses of NS-398 and celecoxib, given 24 h after ischemic PC, completely blocked the cardioprotective effects of late PC against both myocardial stunning and myocardial infarction, indicating that COX-2 activity is necessary for this phenomenon to occur. Neither NS-398 nor celecoxib lowered PGE 2 or 6-keto-PGF1␣ levels in the nonischemic region of preconditioned rabbits, indicating that constitutive COX-1 activity was unaffected. Taken together, these results demonstrate that, in conscious rabbits, up-regulation of COX-2 plays an essential role in the cardioprotection afforded by the late phase of ischemic PC. Therefore, this study identifies COX-2 as a cardioprotective protein. The analysis of arachidonic acid metabolites strongly points to PGE 2 and͞or PGI2 as the likely effectors of COX-2-dependent protection. The recognition that COX-2 mediates the antistunning and antiinfarct effects of late PC impels a reassessment of current views regarding this enzyme, which is generally regarded as detrimental.

Journal of the American College of Cardiology, 2003

The goal of this study was to investigate the effect of three different doses of acetylsalicylic ... more The goal of this study was to investigate the effect of three different doses of acetylsalicylic acid (aspirin) (ASA) on the late phase of ischemic preconditioning (PC) against myocardial stunning. Although recent evidence indicates that the late phase of ischemic PC is mediated by cyclooxygenase-2 (COX-2), the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit COX-2 activity on late PC has not been evaluated; ASA is the most widely used NSAID. Therefore, we determined whether ASA impedes the development of late PC. Conscious rabbits underwent a protocol consisting of three days of six 4-min coronary occlusion/4-min reperfusion cycles. Neither 5 mg/kg nor 10 mg/kg x 3 of ASA interfered with the protective effects of late PC against stunning. In contrast, the late PC effect was completely abrogated by 25 mg/kg of ASA. Low-dose (5 mg/kg) ASA effectively inhibited platelet aggregation but did not prevent the increase in COX-2 activity, whereas the highest dose (25 mg/kg) completely blocked COX-2 activity. The administration of ASA either at antithrombotic doses (5 mg/kg), which are widely used to prevent cardiovascular events in patients, or at analgesic/antipyretic doses (10 mg/kg) does not interfere with the cardioprotective effects of late PC against myocardial stunning. In contrast, high doses of ASA (25 mg/kg), which are used as antirheumatic therapy, abrogate both COX-2 activity and late PC, suggesting that nonselective doses of NSAIDs should be used with caution in patients with atherosclerotic cardiovascular disease because they may deprive the heart of its innate defensive response.

Journal of the American College of Cardiology, 2003

Journal of Molecular and Cellular Cardiology, 2005

Ischemic tolerance decreases with aging and the cardioprotective effect of ischemic preconditioni... more Ischemic tolerance decreases with aging and the cardioprotective effect of ischemic preconditioning (IPC) is impaired in aged animals. Although lifelong caloric restriction (CR) profoundly affects the physiological and pathophysiological modifications induced by aging and markedly increases life span in several species, it is unclear whether short-term CR affects ischemic tolerance and IPC in aged hearts. Sixmonth-old (Y) and 24-month-old (O) Fischer 344 male rats were randomly divided into two groups; AL rats were fed ad libitum, whereas CR rats were fed 90% of the caloric intake of AL for 2 weeks followed by 65% of the caloric intake for 2 weeks. Isolated perfused hearts were subjected to 25 min of ischemia followed by 30 min of reperfusion with or without IPC. The recovery of LV function after reperfusion improved with IPC in ALY but not in ALO. CR improved the recovery of LV function in both CRY and CRO but the cardioprotective effect of IPC was not additive to that of CR. Neither 5-hydroxydecanoate nor glibenclamide abrogated the protective effect of CR in either CRY or CRO. The recovery of myocardial high-energy phosphates after reperfusion was better with CR in both generations. There was no difference in myocardial expression levels of AMP-activated kinase (AMPK) but AMPK-a phosphorylated at Thr 172 increased with CR in both Y and O. In conclusion, short-term CR improves myocardial ischemic tolerance independent of the opening of KATP channels in both Y and O. CR-induced cardioprotection is associated with an increase in activated AMPK.

Journal of Molecular and Cellular Cardiology, 2011

Approximately half of older patients with congestive heart failure have normal left ventricular (... more Approximately half of older patients with congestive heart failure have normal left ventricular (LV) systolic but abnormal LV diastolic function. In mammalian hearts, aging is associated with LV diastolic dysfunction. Caloric restriction (CR) is expected to retard cellular senescence and to attenuate the physiological decline in organ function. Therefore, the aim of the present study was to investigate the impact of long-term CR on cardiac senescence, in particular the effect of CR on LV diastolic dysfunction associated with aging. Male 8month-old Fischer344 rats were divided into ad libitum fed and CR (40% energy reduction) groups. LV function was evaluated by echocardiography and cardiac senescence was compared between the two groups at the age of 30-month-old. (1) Echocardiography showed similar LV systolic function, but better LV diastolic function in the CR group. (2) Histological analysis revealed that CR attenuated the accumulation of senescence-associated β-galactosidase and lipofuscin and reduced myocyte apoptosis. (3) In measurements of [Ca 2+ ] i transients, the time to 50% relaxation was significantly smaller in the CR group, whereas F/F 0 was similar. (4) CR attenuated the decrease in sarcoplasmic reticulum calcium ATPase 2 protein with aging. (5) CR suppressed the mammalian target of rapamycin (mTOR) pathway and increased the ratio of conjugated to cytosolic light chain 3, suggesting that autophagy is enhanced in the CR hearts. In conclusion, CR improves diastolic function in the senescent myocardium by amelioration of the age-associated deterioration in intracellular Ca 2+ handling. Enhanced autophagy via the suppression of mTOR during CR may retard cardiac senescence.

Journal of Molecular and Cellular Cardiology, 1998

A role for adenosine in ischemic preconditioning and hypoxic preconditioning (HP) has been establ... more A role for adenosine in ischemic preconditioning and hypoxic preconditioning (HP) has been established in several species but is controversial in rats, due in part to the inconsistency of the data from the different experimental design. Our objective was to investigate the role of adenosine in the protection of the ischemic myocardium by HP in rats. perfused hearts isolated from Sprague-Dawley rats were exposed to 5 min of hypoxic perfusion before 25 min of global ischemia followed by 20 min of reperfusion. The effects of adenosine receptor antagonist, 8-(p-sulfophenyl)-theophylline (8SPT) on HP-based changes in left-ventricular function, energy metabolites, and release of creatine kinase and lactate dehydrogenase were determined. To minimise non-specific effects of 8SPT, low concentrations of agent (0.5 or 1.0 micro mol/l) were used. 8SPT alone had no deleterious effects on normoxically perfused hearts or on ischemic/reperfused hearts. HP improved the recovery of LV function and creatine phosphate, and reduced the release of enzymes during reperfusion. 8SPT (1.0 micromol/l) ameliorated the beneficial effect of HP on cardiac function, but did not reverse the reduction in release of enzymes by HP completely. results suggest that the protective effect of HP on myocardial contractile function may be mediated by receptor(s) that can be inhibited by low concentrations of antagonist but may not have a primary role in the reduction of cellular damage by HP in rats.

Journal of Clinical Investigation, 2009

Cardiovascular research, Jan 8, 2015

Circulation, Oct 28, 2008

Japanese Circulation Journal, Jun 20, 1995

Japanese Heart Journal, Oct 1, 2000

ABSTRACT

The American journal of physiology

The American journal of physiology, 1999

American journal of physiology. Heart and circulatory physiology, 2002

American journal of physiology. Heart and circulatory physiology, 2003

Circulation research, Jan 9, 2002

Proceedings of the National Academy of Sciences, 2000

Journal of the American College of Cardiology, 2003

Journal of Molecular and Cellular Cardiology, 2005

Journal of Molecular and Cellular Cardiology, 2011

Journal of Molecular and Cellular Cardiology, 1998