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Takahito Tamai,
Osamu Yamaguchi,
Shungo Hikoso,
Toshihiro Takeda,
Manabu Taneike,
Takafumi Oka,
Jota Oyabu,
Tomokazu Murakawa,
Hiroyuki Nakayama,
Yoshihiro Uno,
Kyoji Horie, Kazuhiko Nishida,
Nahum Sonenberg,
Ajay M Shah,
Junji Takeda,
Issei Komuro,
Kinya Otsu
[show abstract]
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ABSTRACT: Cardiomyocytes proliferate during fetal life, but lose their ability to proliferate soon after birth and further increases in cardiac mass are achieved through an increase in cell size or hypertrophy. Mammalian target of rapamycin complex 1 (mTORC1) is critical for cell growth and proliferation. Rheb (Ras homologue enriched in brain) is one of the most important upstream regulators of mTORC1. Here, we attempted to clarify the role of Rheb in the heart using cardiac-specific Rheb-deficient mice (Rheb(-/-)). Rheb(-/-) mice died from postnatal day 8 to 10. The heart-to-body weight ratio, an index of cardiomyocyte hypertrophy, in Rheb(-/-) was lower than that in the control (Rheb(+/+)) at postnatal day 8. The cell surface area of cardiomycytes isolated from the mouse hearts increased from postnatal day 5 to 8 in Rheb(+/+) mice, but not in Rheb(-/-) mice. Ultrastructural analysis indicated that sarcomere maturation was impaired in Rheb(-/-) hearts during the neonatal period. Rheb(-/-) hearts exhibited no difference in the phosphorylation level of S6 or 4E-BP1, downstream of mTORC1, at postnatal day 3, but showed attenuation at postnatal day 5 or 8 compared to the control. Polysome analysis revealed that the mRNA translation activity decreased in Rheb(-/-) hearts at postnatal day 8. Futhermore, ablation of eukaryotic initiation factor 4E-binding protein 1 in Rheb(-/-) mice improved mRNA translation, cardiac hypertrophic growth, sarcomere maturation and survival. Thus, Rheb-dependent mTORC1 activation becomes essential for cardiomyocyte hypertrophic growth after early postnatal period.
Journal of Biological Chemistry 02/2013; · 4.77 Impact Factor
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Takafumi Oka,
Shungo Hikoso,
Osamu Yamaguchi,
Manabu Taneike,
Toshihiro Takeda,
Takahito Tamai,
Jota Oyabu,
Tomokazu Murakawa,
Hiroyuki Nakayama, Kazuhiko Nishida,
Shizuo Akira,
Akitsugu Yamamoto,
Issei Komuro,
Kinya Otsu
Nature 09/2012; · 36.28 Impact Factor
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Takafumi Oka,
Shungo Hikoso,
Osamu Yamaguchi,
Manabu Taneike,
Toshihiro Takeda,
Takahito Tamai,
Jota Oyabu,
Tomokazu Murakawa,
Hiroyuki Nakayama, Kazuhiko Nishida,
Shizuo Akira,
Akitsugu Yamamoto,
Issei Komuro,
Kinya Otsu
[show abstract]
[hide abstract]
ABSTRACT: Heart failure is a leading cause of morbidity and mortality in industrialized countries. Although infection with microorganisms is not involved in the development of heart failure in most cases, inflammation has been implicated in the pathogenesis of heart failure. However, the mechanisms responsible for initiating and integrating inflammatory responses within the heart remain poorly defined. Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA. Mitochondria damaged by external haemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes. Here we show that mitochondrial DNA that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis and dilated cardiomyopathy. Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions, but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload. Early in the pathogenesis, DNase II-deficient hearts showed infiltration of inflammatory cells and increased messenger RNA expression of inflammatory cytokines, with accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium. Administration of inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA, or ablation of Tlr9 attenuated the development of cardiomyopathy in DNase II-deficient mice. Furthermore, Tlr9 ablation improved pressure overload-induced cardiac dysfunction and inflammation even in mice with wild-type Dnase2a alleles. These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.
Nature 04/2012; 485(7397):251-5. · 36.28 Impact Factor
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Manabu Taneike,
Isamu Mizote,
Takashi Morita,
Tetsuya Watanabe,
Shungo Hikoso,
Osamu Yamaguchi,
Toshihiro Takeda,
Takafumi Oka,
Takahito Tamai,
Jota Oyabu,
Tomokazu Murakawa,
Hiroyuki Nakayama, Kazuhiko Nishida,
Junji Takeda,
Naoki Mochizuki,
Issei Komuro,
Kinya Otsu
[show abstract]
[hide abstract]
ABSTRACT: Calpains make up a family of Ca(2+)-dependent intracellular cysteine proteases that include ubiquitously expressed μ- and m-calpains. Both are heterodimers consisting of a distinct large catalytic subunit (calpain 1 for μ-calpain and calpain 2 for m-calpain) and a common regulatory subunit (calpain 4). The physiological roles of calpain remain unclear in the organs, including the heart, but it has been suggested that calpain is activated by Ca(2+) overload in diseased hearts, resulting in cardiac dysfunction. In this study, cardiac-specific calpain 4-deficient mice were generated to elucidate the role of calpain in the heart in response to hemodynamic stress. Cardiac-specific deletion of calpain 4 resulted in decreased protein levels of calpains 1 and 2 and showed no cardiac phenotypes under base-line conditions but caused left ventricle dilatation, contractile dysfunction, and heart failure with interstitial fibrosis 1 week after pressure overload. Pressure-overloaded calpain 4-deficient hearts took up a membrane-impermeant dye, Evans blue, indicating plasma membrane disruption. Membrane repair assays using a two-photon laser-scanning microscope revealed that calpain 4-deficient cardiomyocytes failed to reseal a plasma membrane that had been disrupted by laser irradiation. Thus, the data indicate that calpain protects the heart from hemodynamic stresses, such as pressure overload.
Journal of Biological Chemistry 07/2011; 286(37):32170-7. · 4.77 Impact Factor
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ABSTRACT: Nuclei are anatomical units of the central nervous system (CNS). Their formation sets the structural basis for the functional organization of the brain, a process known as nucleogenesis. In the present study, we investigated the role of the transmembrane immunoglobulin superfamily molecule Neph2 in the nucleogenesis of the pontine nucleus (PN). Neph2 expression is turned on in migrating PN neurons only after they enter the presumptive nuclear region. Neph2 knockdown disrupted the nuclear organization of PN presumably by changing the migratory behavior of PN neurons inside the nuclear region. Moreover, overexpression of the cytoplasmic region of Neph2, which can sequester intracellular signaling of endogenous Neph2, resulted in similar phenotypes. Overall, these results suggest Neph2 is involved in the nucleogenesis of the PN through the control of neuronal migration inside the nucleus.
Molecular and Cellular Neuroscience 01/2011; 46(3):662-70. · 3.66 Impact Factor
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Manabu Taneike,
Osamu Yamaguchi,
Atsuko Nakai,
Shungo Hikoso,
Toshihiro Takeda,
Isamu Mizote,
Takafumi Oka,
Takahito Tamai,
Jota Oyabu,
Tomokazu Murakawa, Kazuhiko Nishida,
Takahiko Shimizu,
Masatsugu Hori,
Issei Komuro,
Takuji Shirasawa Takuji Shirasawa,
Noboru Mizushima,
Kinya Otsu
[show abstract]
[hide abstract]
ABSTRACT: Constitutive autophagy is important for control of the quality of proteins and organelles to maintain cell function. Damaged proteins and organelles accumulate in aged organs. We have previously reported that cardiac-specific Atg5 (autophagy-related gene 5)-deficient mice, in which the gene was floxed out early in embryogenesis, were born normally, and showed normal cardiac function and structure up to 10 weeks old. In the present study, to determine the longer-term consequences of Atg5-deficiency in the heart, we monitored cardiac-specific Atg5-deficient mice for further 12 months. First, we examined the age-associated changes of autophagy in the wild-type mouse heart. The level of autophagy, as indicated by decreased LC3-II (microtubule-associated protein 1 light chain 3-II) levels, in the hearts of 6-, 14- or 26-month-old mice was lower than that of 10-week-old mice. Next, we investigated the cardiac function and life-span in cardiac-specific Atg5-deficient mice. The Atg5-deficient mice began to die after the age of 6 months. Atg5-deficient mice exhibited a significant increase in left ventricular dimension and decrease in fractional shortening of the left ventricle at the age of 10 months, compared to control mice, while they showed similar chamber size and contractile function at the age of 3 months. Ultrastructural analysis revealed a disorganized sarcomere structure and collapsed mitochondria in 3- and 10-month-old Atg5-deficient mice, with decreased mitochondrial respiratory functions. These results suggest that continuous constitutive autophagy has a crucial role in maintaining cardiac structure and function.
Autophagy 07/2010; 6(5):600-6. · 7.45 Impact Factor
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ABSTRACT: Ptf1a, a basic helix-loop-helix transcription factor, plays an indispensable role for cell fate specification of subsets of neurons in the developing central nervous system. However, downstream molecules induced by Ptf1a during neural development have not been well characterized. In the present study, we identified immunoglobulin superfamily molecules, Nephrin and Neph3, as direct downstream targets of Ptf1a. First, the expression domains of Nephrin and Neph3 closely resembled those of Ptf1a in the developing retina, hypothalamus, cerebellum, hindbrain, and spinal cord. Second, Ptf1a bound directly to a PTF-binding motif in the 5'-flanking region of Nephrin and Neph3 genes. Third, Ptf1a activated transcription driven by the 5'-flanking region of these genes. Finally, the expression of Nephrin and Neph3 was lost in Ptf1a-null mice, whereas ectopic expression of Nephrin and Neph3 was induced by forced expression of Ptf1a. We provided further evidence that Nephrin and Neph3 could interact homophilically and heterophilically, suggesting that Nephrin and Neph3 might regulate certain developmental aspects of Ptf1a-positive neurons as homo- or heterooligomers.
Journal of Biological Chemistry 11/2009; 285(1):373-80. · 4.77 Impact Factor
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Isamu Mizote,
Osamu Yamaguchi,
Shungo Hikoso,
Toshihiro Takeda,
Manabu Taneike,
Takafumi Oka,
Takahito Tamai,
Jota Oyabu,
Yasushi Matsumura, Kazuhiko Nishida,
Issei Komuro,
Masatsugu Hori,
Kinya Otsu
[show abstract]
[hide abstract]
ABSTRACT: MTK1 (MEKK4) is a mitogen-activated protein kinase kinase kinase that regulates the activity of its downstream mitogen-activated kinases, p38, and c-Jun N-terminal kinase (JNK). However, the physiological function of MTK1 in the heart remains to be determined. Here, we attempted to elucidate the function of MTK1 in the heart using in vitro and in vivo models. MTK1 was activated in the hearts of mice subjected to pressure overload-induced heart failure. Overexpression of a constitutively active mutant of MTK1 (MTK1DeltaN) induced apoptosis in isolated neonatal rat cardiomyocytes, whereas a kinase domain-deleted form of MTK1 attenuated H(2)O(2)-induced apoptosis. Specific inhibitors of p38 or JNK effectively protected cardiomyocytes from MTK1DeltaN-induced cell death. In mice, cardiac-specific overexpression of MTK1DeltaN resulted in early mortality compared with the lifespan of littermate controls. Echocardiographic analysis revealed increases in end-diastolic and end-systolic left ventricular internal dimensions and a decrease in fractional shortening in MTK1DeltaN transgenic mice. In addition, the mice showed characteristic phenotypes of heart failure such as an increase in lung weight. The number of TUNEL-positive myocytes and the level of cleaved caspase 3 protein were both increased in MTK1DeltaN transgenic mice. Thus, MTK1 plays an important role in the regulation of cell death and is also involved in the pathogenesis of heart failure.
Journal of Molecular and Cellular Cardiology 10/2009; 48(2):302-9. · 5.17 Impact Factor
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Shungo Hikoso,
Osamu Yamaguchi,
Yuko Nakano,
Toshihiro Takeda,
Shigemiki Omiya,
Isamu Mizote,
Manabu Taneike,
Takafumi Oka,
Takahito Tamai,
Jota Oyabu,
Yoshihiro Uno,
Yasushi Matsumura, Kazuhiko Nishida,
Keiichiro Suzuki,
Mikihiko Kogo,
Masatsugu Hori,
Kinya Otsu
[show abstract]
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ABSTRACT: Cardiomyocyte death plays an important role in the pathogenesis of heart failure. The nuclear factor (NF)-kappaB signaling pathway regulates cell death, however, the effect of NF-kappaB pathway on cell death can vary in different cells or stimuli. The purpose of the present study was to clarify the in vivo role of the NF-kappaB pathway in response to pressure overload. First, we subjected C57Bl6/J mice to pressure overload by means of transverse aortic constriction (TAC) and examined the activity of the NF-kappaB pathway in response to pressure overload. IkappaB kinase (IKK) and NF-kappaB were activated after TAC. Then, we investigated the role of the activation using cardiac-specific IKKbeta-deficient mice (CKO). CKO displayed normal global cardiac structure and function compared with control littermates. We subjected CKO and control mice to pressure overload. One week after TAC, CKO showed cardiac dilation, dysfunction, and lung congestion, which are characteristics of heart failure. The number of apoptotic cells in the hearts of CKO mice increased significantly after TAC. The levels of manganese superoxide dismutase mRNA and protein expression in CKO after TAC were significantly attenuated compared with control mice. The levels of oxidative stress and c-Jun N-terminal kinase (JNK) activation in CKO after TAC were significantly greater than those in control mice. Isoproterenol-induced cell death of isolated adult CKO cardiomyocytes was inhibited by treatment with either a manganese superoxide dismutase mimetic or a JNK inhibitor. Thus, the IKKbeta/NF-kappaB signaling pathway plays a protective role in cardiomyocytes because of the attenuation of oxidative stress and JNK activation in a setting of acute pressure overload.
Circulation Research 06/2009; 105(1):70-9. · 9.49 Impact Factor
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Atsushi Tamada,
Tatsuro Kumada,
Yan Zhu,
Tomoko Matsumoto,
Yumiko Hatanaka,
Keiko Muguruma,
Zhe Chen,
Yasuto Tanabe,
Makio Torigoe,
Kenta Yamauchi,
Hiroshi Oyama, Kazuhiko Nishida,
Fujio Murakami
[show abstract]
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ABSTRACT: Robo1, Robo2 and Rig-1 (Robo3), members of the Robo protein family, are candidate receptors for the chemorepellents Slit and are known to play a crucial role in commissural axon guidance in the spinal cord. However, their roles at other axial levels remain unknown. Here we examine expression of Robo proteins by cerebellofugal (CF) commissural axons in the rostral hindbrain and investigate their roles in CF axon pathfinding by analysing Robo knockout mice.
We analysed the expression of Robo proteins by CF axons originating from deep cerebellar neurons in rodent embryos, focusing on developmental stages of their midline crossing and post-crossing navigation. At the stage of CF axon midline crossing, mRNAs of Robo1 and Robo2 are expressed in the nuclear transitory zone of the cerebellum, where the primordium of the deep cerebellar nuclei are located, supporting the notion that CF axons express Robo1 and Robo2. Indeed, immunohistochemical analysis of CF axons labelled by electroporation to deep cerebellar nuclei neurons indicates that Robo1 protein, and possibly also Robo2 protein, is expressed by CF axons crossing the midline. However, weak or no expression of these proteins is found on the longitudinal portion of CF axons. In Robo1/2 double knockout mice, many CF axons reach the midline but fail to exit it. We find that CF axons express Rig-1 (Robo3) before they reach the midline but not after the longitudinal turn. Consistent with this in vivo observation, axons elicited from a cerebellar explant in co-culture with a floor plate explant express Rig-1. In Rig-1 deficient mouse embryos, CF axons appear to project ipsilaterally without reaching the midline.
These results indicate that Robo1, Robo2 or both are required for midline exit of CF axons. In contrast, Rig-1 is required for their approach to the midline. However, post-crossing up-regulation of these proteins, which plays an important role in spinal commissural axon guidance, does not appear to be required for the longitudinal navigation of CF axons after midline crossing. Our results illustrate that although common mechanisms operate for midline crossing at different axial levels, significant variation exists in post-crossing navigation.
Neural Development 12/2008; 3:29. · 3.70 Impact Factor
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Shigemiki Omiya,
Shungo Hikoso,
Yukiko Imanishi,
Atsuhiro Saito,
Osamu Yamaguchi,
Toshihiro Takeda,
Isamu Mizote,
Takafumi Oka,
Manabu Taneike,
Yuko Nakano,
Yasushi Matsumura, Kazuhiko Nishida,
Yoshiki Sawa,
Masatsugu Hori,
Kinya Otsu
[show abstract]
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ABSTRACT: Ferritin heavy chain (FHC) protein was significantly reduced in murine failing hearts following left coronary ligation or thoracic transverse aortic constriction. The mRNA expression of FHC was not significantly altered in failing hearts, compared to that in control sham-operated hearts. Prussian blue staining revealed spotty iron depositions in myocardial infarct failing hearts. Oxidative stress was enhanced in the myocardial infarct failing hearts, as evidenced by increases in 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine immunoreactivity. To clarify the functional significance of FHC downregulation in hearts, we infected rat neonatal cardiomyocytes with adenoviral vector expressing short hairpin RNA targeted to FHC (Ad-FHC-RNAi). The downregulation of FHC induced a reduction in the viability of cardiomyocytes. The relative number of iron deposition-, 4-hydroxy-2-nonenal- or 8-hydroxy-2'-deoxyguanosine-positive cardiomyocytes was significantly higher in Ad-FHC-RNAi-infected cardiomyocytes than in control vector-infected cardiomyocytes. Treatment of Ad-FHC-RNAi-infected cardiomyocytes with desferrioxamine, an iron chelator, significantly reduced the number of iron, 4-hydroxy-2-nonenal or 8-hydroxy-2'-deoxyguanosine-positive cells, and increased viability. In addition, treatment with N-acetyl cysteine, an antioxidant, significantly reduced the number of 4-hydroxy-2-nonenal- or 8-hydroxy-2'-deoxyguanosine-positive cells. Reduced viability in Ad-FHC-RNAi-infected cardiomyocytes was significantly improved with N-acetyl cysteine treatment. These findings indicate that excessive free iron and the resultant enhanced oxidative stress caused by downregulation of FHC lead to cardiomyocyte death. The decrease in FHC expression in failing hearts may play an important role in the pathogenesis of heart failure.
Journal of Molecular and Cellular Cardiology 11/2008; 46(1):59-66. · 5.17 Impact Factor
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ABSTRACT: Heart failure (HF) has become the dominant cardiovascular disorder in the Western world and Japan, so there is an urgent need to clarify the mechanisms governing pathological remodeling mediated through cell death, and to identify ways of preventing and treating HF. Historically, there are 3 types of cell death: apoptosis, autophagy and necrosis. Apoptosis, a form of programmed cell death, has been well characterized and the molecular events involved in apoptotic death are well understood. Necrosis is often defined in a negative manner: death lacking the characteristics of programmed cell death and thus accidental and uncontrolled. However, recent studies indicate that necrosis is tightly regulated. Autophagy is a cell survival mechanism that involves degradation and recycling of cytoplasmic components. In contrast to the other 2 mechanisms, autophagy may mediate cell death under specific circumstances. In fact, damaged cardiomyocytes that show characteristics of autophagy have been observed during HF. However, a recent study indicated that upregulation of autophagy in the failing heart is an adaptive response. This review summarizes recent findings regarding the molecular mechanisms of cardiomyocyte cell death in HF.
Circulation Journal 10/2008; 72 Suppl A:A17-21. · 3.77 Impact Factor
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ABSTRACT: Autophagy is a cell survival mechanism that involves degradation and recycling of cytoplasmic components, such as long-lived proteins and organelles. In addition, autophagy mediates cell death under specific circumstances. Apoptosis, a form of programmed cell death, has been well characterized, and the molecular events involved in apoptotic death are well understood. Damaged cardiomyocytes that show characteristics of autophagy have been observed during heart failure. However, it remains unclear whether autophagy is a sign of failed cardiomyocyte repair or is a suicide pathway for the failing cardiomyocytes. Although autophagy and apoptosis are markedly different processes, several pathways regulate both autophagic and apoptotic machinery and autophagy can cooperate with apoptosis. This review summarizes the evidence for crosstalk between autophagy and apoptosis.
Circulation Research 09/2008; 103(4):343-51. · 9.49 Impact Factor
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Tetsuya Watanabe,
Toshihiro Takeda,
Shigemiki Omiya,
Shungo Hikoso,
Osamu Yamaguchi,
Yuko Nakano,
Yoshiharu Higuchi,
Atsuko Nakai,
Yusuke Abe,
Yayoi Aki-Jin,
Masayuki Taniike,
Isamu Mizote,
Yasushi Matsumura,
Takahiko Shimizu, Kazuhiko Nishida,
Kiyohiro Imai,
Masatsugu Hori,
Takuji Shirasawa,
Kinya Otsu
[show abstract]
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ABSTRACT: This study examined whether a reduction in hemoglobin-oxygen affinity improves exercise capacity in mice with heart failure.
Exercise intolerance is a major determinant of quality of life in patients with chronic heart failure. One of the major goals of the treatment for chronic heart failure is to improve quality of life.
Four weeks after left coronary ligation, we transplanted bone marrow cells isolated from the transgenic mice expressing a hemoglobin variant with low oxygen affinity, Presbyterian, into the lethally irradiated mice with heart failure or administered a synthetic allosteric modifier of hemoglobin. The mice were then exercised on a treadmill.
Four weeks after the left coronary artery ligation, mice showed cardiac dysfunction and chamber dilation, which were characteristics of heart failure. The transplantation led to a reduction in hemoglobin-oxygen affinity and an increase in oxygen supply for skeletal muscle without changes in muscle properties. The transplanted mice showed improved running performance on a treadmill despite impaired cardiac contractility. Furthermore, administration of the synthetic allosteric modifier of hemoglobin showed a similar effect.
Allosteric modification of hemoglobin represents a therapeutic option for improving exercise capacity in patients with chronic heart failure. One mechanism of improvement in exercise capacity is enhanced oxygen delivery in the skeletal muscle.
Journal of the American College of Cardiology 09/2008; 52(9):779-86. · 14.16 Impact Factor
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Masayuki Taniike,
Osamu Yamaguchi,
Ikuko Tsujimoto,
Shungo Hikoso,
Toshihiro Takeda,
Atsuko Nakai,
Shigemiki Omiya,
Isamu Mizote,
Yuko Nakano,
Yoshiharu Higuchi,
Yasushi Matsumura, Kazuhiko Nishida,
Hidenori Ichijo,
Masatsugu Hori,
Kinya Otsu
[show abstract]
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ABSTRACT: Mechanical stress on the heart can lead to crucially different outcomes. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy, characterized by a normal cardiac structure and normal or enhanced cardiac function. Pathological stimuli such as hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Apoptosis signal-regulating kinase 1 (ASK1) is known to be involved in pathological cardiac remodeling, but it has not been determined whether ASK1 pathways coordinate the signaling cascade leading to physiological type cardiac growth.
To evaluate the role of ASK1 in the physiological form of cardiac growth, mice lacking ASK1 (ASK1-/-) were exercised by swimming for 4 weeks. ASK1-/- mice showed exaggerated growth of the heart accompanied by typical characteristics of physiological hypertrophy. Their swimming-induced activation of Akt, a key molecule in the signaling cascade of physiological hypertrophy, increased more than that seen in wild-type controls. The activation of p38, a downstream kinase of ASK1, was suppressed selectively in the swimming-exercised ASK1-/- mice. Furthermore, the inhibition of ASK1 or p38 activity enhanced insulin-like growth factor 1-induced protein synthesis in rat neonatal ventricular cardiomyocytes, and the treatment with a specific inhibitor of p38 resulted in enhancement of Akt activation and suppression of protein phosphatase 2A activation. The cardiac-specific p38alpha-deficient mice developed an exacerbated form of cardiac hypertrophy in response to swimming exercise.
These results indicate that the ASK1/p38 signaling pathway negatively regulates physiological hypertrophy.
Circulation 02/2008; 117(4):545-52. · 14.74 Impact Factor
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Shungo Hikoso,
Yasuhiro Ikeda,
Osamu Yamaguchi,
Toshihiro Takeda,
Yoshiharu Higuchi,
Shinichi Hirotani,
Kazunori Kashiwase,
Michio Yamada,
Michio Asahi,
Yasushi Matsumura, Kazuhiko Nishida,
Masunori Matsuzaki,
Masatsugu Hori,
Kinya Otsu
[show abstract]
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ABSTRACT: We examined whether the inhibition of apoptosis signal-regulating kinase 1 (ASK1) would attenuate the progression of heart failure in TO-2 hamsters with hereditary dilated cardiomyopathy.
Heart failure remains the leading cause of mortality and requires novel therapies targeting the biologically relevant processes within cardiomyocytes that lead to cell death. Apoptosis signal-regulating kinase 1 is a key signaling molecule for cardiomyocyte death.
We generated recombinant adeno-associated virus (rAAV) expressing an N-terminal truncated form of the dominant-negative mutant of ASK1 (ASKdeltaN(KR)). TO-2 hamsters were subjected to an in vivo rAAV transcoronary transfer.
ASKdeltaN(KR) retained its dominant-negative activity in vitro. The rAAV expressing ASKdeltaN(KR) treatment inhibited ASK1 activation in the hamster hearts and suppressed progression of ventricular remodeling such as chamber dilation, impairment of contractile and relaxation functions, and fibrosis. Inhibition of ASK1 reduced the number of apoptotic cells and selectively attenuated c-Jun NH2-terminal kinase activation. Although the deficiency of delta-sarcoglycan, a genetic defect in the hamster, leads to the degradation of dystrophin, the treatment significantly protected hearts from this degradation, probably by inhibiting calpain activation.
Apoptosis signal-regulating kinase 1 is involved in the pathogenesis of heart failure progression, mediated through c-Jun NH2-terminal kinase-mediated apoptosis and calpain-dependent dystrophin cleavage, and may be a therapeutic target to treat patients with heart failure.
Journal of the American College of Cardiology 08/2007; 50(5):453-62. · 14.16 Impact Factor
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Atsuko Nakai,
Osamu Yamaguchi,
Toshihiro Takeda,
Yoshiharu Higuchi,
Shungo Hikoso,
Masayuki Taniike,
Shigemiki Omiya,
Isamu Mizote,
Yasushi Matsumura,
Michio Asahi, Kazuhiko Nishida,
Masatsugu Hori,
Noboru Mizushima,
Kinya Otsu
[show abstract]
[hide abstract]
ABSTRACT: Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells. Although altered autophagy has been observed in various heart diseases, including cardiac hypertrophy and heart failure, it remains unclear whether autophagy plays a beneficial or detrimental role in the heart. Here, we report that the cardiac-specific loss of autophagy causes cardiomyopathy in mice. In adult mice, temporally controlled cardiac-specific deficiency of Atg5 (autophagy-related 5), a protein required for autophagy, led to cardiac hypertrophy, left ventricular dilatation and contractile dysfunction, accompanied by increased levels of ubiquitination. Furthermore, Atg5-deficient hearts showed disorganized sarcomere structure and mitochondrial misalignment and aggregation. On the other hand, cardiac-specific deficiency of Atg5 early in cardiogenesis showed no such cardiac phenotypes under baseline conditions, but developed cardiac dysfunction and left ventricular dilatation one week after treatment with pressure overload. These results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagy in failing hearts is an adaptive response for protecting cells from hemodynamic stress.
Nature Medicine 06/2007; 13(5):619-24. · 22.46 Impact Factor
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Atsuko Nakai,
Osamu Yamaguchi,
Toshihiro Takeda,
Yoshiharu Higuchi,
Shungo Hikoso,
Masayuki Taniike,
Shigemiki Omiya,
Isamu Mizote,
Yasushi Matsumura,
Michio Asahi, Kazuhiko Nishida,
Masatsugu Hori,
Noboru Mizushima,
Kinya Otsu
[show abstract]
[hide abstract]
ABSTRACT: Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells
Nature Medicine 04/2007; 13(5):619-624. · 22.46 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Classic cadherins are calcium dependent homophilic cell adhesion molecules that play a key role in developmental processes such as morphogenesis, compartmentalization and maintenance of a tissue. They also play important roles in development and function of the nervous system. Although classic cadherins have been shown to be involved in the migration of non-neuronal cells, little is known about their role in neuronal migration. Here, we show that classic cadherins are essential for the migration of precerebellar neurons. In situ hybridization analysis shows that at least four classic cadherins, cadherin 6 (Cad6), cadherin 8 (Cad8), cadherin11 (Cad11) and N-cadherin (Ncad), are expressed in the migratory streams of lateral reticular nucleus and external cuneate nucleus (LRN/ECN) neurons. Functional analysis performed by electroporation of cadherin constructs into the hindbrain indicates requirement for cadherins in the migration of LRN/ECN neurons both in vitro and in vivo. While overexpression of full-length classic cadherins, NCAD and CAD11, has no effect on LRN/ECN neuron migration, overexpression of two dominant negative (DN) constructs, membrane-bound form and cytoplasmic form, slows it down. Introduction of a DN construct does not alter some characteristics of LRN/ECN cells as indicated by a molecular marker, TAG1, and their responsiveness to chemotropic activity of the floor plate (FP). These results suggest that classic cadherins contribute to contact-dependent mechanisms of precerebellar neuron migration probably via their adhesive property.
Development 06/2006; 133(10):1923-31. · 6.60 Impact Factor
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Toshihiro Takeda,
Michio Asahi,
Osamu Yamaguchi,
Shungo Hikoso,
Hiroyuki Nakayama,
Yoichiro Kusakari,
Makoto Kawai,
Kenichi Hongo,
Yoshiharu Higuchi,
Kazunori Kashiwase, [......],
Masayuki Taniike,
Atsuko Nakai, Kazuhiko Nishida,
Satoshi Kurihara,
Dorit B Donoviel,
Alan Bernstein,
Taisuke Tomita,
Takeshi Iwatsubo,
Masatsugu Hori,
Kinya Otsu
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ABSTRACT: Genetic studies of families with familial Alzheimer's disease have implicated presenilin 2 (PS2) in the pathogenesis of this disease. PS2 is ubiquitously expressed in various tissues including hearts. In this study, we examined cardiac phenotypes of PS2 knockout (PS2KO) mice to elucidate a role of PS2 in hearts. PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis. Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased compared with that in their littermate controls. A study of isolated papillary muscle showed that peak amplitudes of Ca2+ transients and peak tension were significantly higher in PS2KO mice than those in their littermate controls. PS2KO mouse hearts exhibited no change in expression of calcium regulatory proteins. Since it has been demonstrated that PS2 in brain interacts with sorcin, which serves as a modulator of cardiac ryanodine receptor (RyR2), we tested whether PS2 also interacts with RyR2. Immmunoprecipitation analysis showed that PS2, sorcin, and RyR2 interact with each other in HEK-293 cells overexpressing these proteins or in mouse hearts. Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin at the Z-lines. Elevated Ca2+ attenuated the association of RyR2 with PS2, whereas the association of sorcin with PS2 was enhanced. The enhanced Ca2+ transients and contractility in PS2KO mice were observed at low extracellular [Ca2+] but not at high levels of [Ca2+]. Taken together, our results suggest that PS2 plays an important role in cardiac excitation-contraction coupling by interacting with RyR2.
The FASEB Journal 01/2006; 19(14):2069-71. · 5.71 Impact Factor
