المؤلفون: Jun Huang, Yan-Ling Sun, Xue Wang, Zheng-Hong Qin, Yi Zhu, Yu-Ting Zhu, Zhe Li, Jun-Chao Wu, Fang Lin, Yan Wang

المصدر: Acta Pharmacol Sin

مصطلحات موضوعية: Genetically modified mouse, medicine.medical_specialty, Cathepsin D, Mice, Transgenic, Article, Cathepsin L, Amyloid beta-Protein Precursor, Mice, Alzheimer Disease, Transcription (biology), Internal medicine, ACSS2, Presenilin-1, PSEN1, medicine, Animals, Humans, Cognitive Dysfunction, Pharmacology (medical), Pharmacology, Amyloid beta-Peptides, biology, business.industry, Brain, General Medicine, Disease Models, Animal, Endocrinology, biology.protein, TFEB, Lysosomes, business, Biogenesis

الوصف: Amyloid-β peptide (Aβ) aggregation is the hallmark of Alzheimer’s disease (AD). The imbalance between the production and clearance of Aβ results in the accumulation and aggregation of Aβ in the brain. Thus far, few drugs are available for AD treatment, but exercise has been recognized for its cognition-enhancing properties in AD patients. The underlying mechanisms remain unclear. Our recent study showed that long-term running exercise could activate the lysosomal function in the brains of mice. In this study, we investigated whether exercise could reduce Aβ accumulation by activating lysosomal function in APP/PSEN1 transgenic mice. Started at the age of 5 months, the mice were trained with a running wheel at the speed of 18 r/min, 40 min/d, 6 d/week for 5 months, and were killed at the end of the 10th month, then brain tissue was collected for biochemical analyses. The cognitive ability was assessed in the 9th month. We showed that long-term exercise significantly mitigated cognitive dysfunction in AD mice, accompanied by the enhanced lysosomal function and the clearance of Aβ in the brain. Exercise significantly promoted the nuclear translocation of transcription factor EB (TFEB), and increased the interaction between nuclear TFEB with AMPK-mediated acetyl-CoA synthetase 2, thus enhancing transcription of the genes associated with the biogenesis of lysosomes. Exercise also raised the levels of mature cathepsin D and cathepsin L, suggesting that more Aβ peptides could be degraded in the activated lysosomes. This study demonstrates that exercise may improve the cognitive dysfunction of AD by enhancing lysosomal function.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2c8f61df5361a27abee082017a05c6f9Test
https://doi.org/10.1038/s41401-021-00720-6Test

المؤلفون: Gui-Ping Wang, Li Luo, Bo Liao, Zheng-Hong Qin, Yu-Long Wang, Shan-Yao Pan, Shuai Hu, Yu Zhang

المصدر: Behavioural Brain Research. 412:113384

مصطلحات موضوعية: Male, medicine.medical_specialty, ATG5, High-Intensity Interval Training, CREB, Hippocampus, Electron Transport, Mice, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Physical Conditioning, Animal, Internal medicine, Mitophagy, Autophagy, medicine, Animals, Aerobic exercise, Aging brain, Respiratory function, Phosphorylation, Cyclic AMP Response Element-Binding Protein, Muscle, Skeletal, 030304 developmental biology, Mice, Inbred ICR, 0303 health sciences, Electron Transport Complex I, biology, business.industry, Brain-Derived Neurotrophic Factor, Age Factors, Mitochondria, Endocrinology, biology.protein, business, High-intensity interval training, 030217 neurology & neurosurgery, Signal Transduction

الوصف: Autophagy is involved in aging-related cognitive impairment. Aerobic exercise training can improve cognitive function in the elderly and this effect may be associated with autophagic mechanisms and mitochondrial respiratory function. High intensity interval training (HIIT) has beneficial effects on heart and skeletal muscles by activating autophagy and/or mitophagy, but the effects of HIIT on autophagy/mitophagy in the aging brain are unknown. This study investigated the effects of HIIT on the mitochondrial respiratory complex and autophagy/mitophagy, and its relation to brain function. Thirteen middle-aged male ICR mice underwent HIIT for 7 weeks. The exercise program reduced the spontaneous behavior and exploration activities of the mice. The phosphorylation level of cAMP response element binding protein (CREB) and the protein expression of brain-derived neurotrophic factor (BDNF) decreased after the 7-week HIIT. Exercise downregulated the protein expression of Complex Ⅰ and upregulated the protein expression of Complex Ⅲ, Complex Ⅳ and Complex Ⅴ. HIIT also decreased the expression of mitophagy-related proteins in the mitochondrial fractions of the hippocampus. However, HIIT did not change the expression of autophagy-related proteins LC3, P62, Atg5, Atg7, Beclin-1 and Lamp2 in the total lysate of the hippocampus. These data indicated that HIIT might have negative effects on the plasticity of the hippocampus in middle-aged mice. The effects may be related to the dysregulation of CREB-BDNF signaling, mitochondrial respiratory complex and mitophagy induced by HIIT.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::07d60f2b5f3b800030a06b1e130593daTest
https://doi.org/10.1016/j.bbr.2021.113384Test

المؤلفون: Xue Wang, Fang Lin, Zheng-Hong Qin, Yu Ting Zhu, Zhe Li, Jun Huang

المصدر: Exercise Biochemistry Review. 1

مصطلحات موضوعية: Cathepsin, Genetically modified mouse, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Autophagy, Cathepsin D, Endocrinology, medicine.anatomical_structure, Western blot, Internal medicine, Lysosome, medicine, PSEN1, TFEB, business

الوصف: Objective Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by aggregation of amyloid-β (Aβ) peptides. Reduction of progressive accumulation of Aβ will delay the progression of AD. As a main digestive organelles in cells, lysosome is crucial to clear the harmful proteins from extracellular and intracellular. Recent evidences have shown that exercise improves cognitive function of AD, but the reason is not very clear. This manuscript is to study the effect of long-term running exercise training on lysosomal function in mouse brain and explore its relationship with the progress of Alzheimer’s disease. Methods the APP/PSEN1 transgenic mice were used as the AD model to examine the relationship between AD, exercise and lysosomes. The mice were trained on a treadmill from the 5 months old, 60 min/day and 5 days/week for 5 months. The Lashley water maze and the novel object recognition test were used to estimate the cognitive ability of the mice; the balance beam and the rotating rod experiment were used to estimate motor coordination. The Aβ accumulation was measured with brain section and immunochemistry. The effects of long-term exercise on lysosomal function of cerebral cortex, striatum and hippocampus were measured. Among them, the autophagy/lysosome associated proteins level was determined by Western blot and the autophagy vacuoles and lysosome were observed through electron microscope. TFEB nuclear translocation was determined by Western blot and Immunofluorescence. The transcription of the TFEB-regulating genes were determined by quantitative PCR (qPCR). Results Long-term exercise improved the cognitive ability and physical coordination of AD transgenic mice. Exercise reduced Aβ accumulation through increase the clearance of Aβ and affected little on the production of Aβ. Exercise, not only increased the colocalization of lysosomes with Aβ, but also increased the mature type of lysosomal protease cathepsin D and cathepsin L. In the meanwhile, exercise promoted the nuclear translocation of TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy, and increased the transcription of genes associated with the biogenesis of lysosome. Conclusions Long-term exercise training delays the progress of Alzheimer's disease through activating function of lysosome and enhancing the biogenesis of lysosome. Exercise may be a therapeutic approach for the treatment of Alzheimer's disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::f1b894d98b65284ebec617faebeee53dTest
https://doi.org/10.14428/ebr.v1i5.13233Test

المؤلفون: Jia-Ru Dai, Shan-Shan Guo, Zheng-Hong Qin, A-Ming Lu, Xiao-Fang Gao, Yan Wang, Zhou Zhu, Lisa Wood, Haidong Xu, Li Luo, Xiao-Fei Zhang, Yan-Rong Gu

المصدر: The journals of gerontology. Series A, Biological sciences and medical sciences. 72(10)

مصطلحات موضوعية: 0301 basic medicine, Male, Aging, medicine.medical_specialty, Immunoblotting, Hippocampus, Fluorescent Antibody Technique, Mitochondrion, medicine.disease_cause, Real-Time Polymerase Chain Reaction, Thiobarbituric Acid Reactive Substances, Rats, Sprague-Dawley, 03 medical and health sciences, Microscopy, Electron, Transmission, Internal medicine, Physical Conditioning, Animal, Mitophagy, medicine, Autophagy, Animals, Cognitive decline, Organelle Biogenesis, business.industry, Rats, Oxidative Stress, 030104 developmental biology, Endocrinology, Biochemistry, Mitochondrial biogenesis, mitochondrial fusion, Proteolysis, Geriatrics and Gerontology, business, Lysosomes, Oxidative stress

الوصف: Exercise improves cognitive function in older adults, but the underlying mechanism is largely unknown. Both lysosomal degradation and mitochondrial quality control decline with age. We hypothesized that exercise ameliorates age-related cognitive decline through the improvement of mitochondrial quality control in aged hippocampus, and this effect is associated with lysosomal proteolysis. Sixteen to eighteen-month old male Sprague Dawley rats underwent swim exercise training for 10 weeks. The exercise regimen prevented cognitive decline in aged rats, reduced oxidative stress, and rejuvenated mitochondria in the aged hippocampus. Exercise training promoted mitochondrial biogenesis, increased mitochondrial fusion and fission, and activated autophagy/mitophagy in aged hippocampal neurons. Lysosomal inhibitor chloroquine partly blocked beneficial effects of exercise on cognitive function, oxidative stress, autophagy/mitophagy, and mitochondrial quality control in aged rats. These results suggest that preservation of cognitive function by long-term exercise is associated with improvement of mitochondrial quality control in aged hippocampus and that lysosomal degradation is required for this process. Our findings suggest that exercise training or pharmacological regulation of mitochondrial quality control and lysosomal degradation may be effective strategies for slowing down age-related cognitive decline.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1c568c4e78fbbff63eda7d5afa130d78Test
https://pubmed.ncbi.nlm.nih.gov/28329063Test

المؤلفون: Shu-Zhi Wang, Zheng-Hong Qin, Jian-Qun Kou, Yin-Li Xu, Qi Zhu

المصدر: Evidence-based Complementary and Alternative Medicine : eCAM
Evidence-Based Complementary and Alternative Medicine, Vol 2015 (2015)

مصطلحات موضوعية: medicine.medical_specialty, Kidney, Proteinuria, Article Subject, biology, business.industry, Renal function, lcsh:Other systems of medicine, lcsh:RZ201-999, medicine.disease, Nephropathy, Nephrin, Endocrinology, medicine.anatomical_structure, Complementary and alternative medicine, Internal medicine, medicine, biology.protein, Hypoalbuminemia, medicine.symptom, business, Nephrotic syndrome, Kidney disease, Research Article

الوصف: Chronic kidney disease (CKD) becomes a global health problem with high morbidity and mortality. Adriamycin- (ADR-) induced rodent chronic nephropathy is a classic experimental model of human minimal lesion nephrotic syndrome. The present study investigated the effect of cobrotoxin (CTX) on ADR-induced nephropathy. Rats were given 6 mg/kg ADR once through the tail vein to replicate ADR nephropathy model. CTX was administered to rats daily by placing a fast dissolving CTX membrane strip under the tongue starting from 5 days prior to ADR administration until the end of experiment. The results showed that CTX ameliorated the symptoms of ADR nephropathy syndrome with reduced body weight loss, proteinuria, hypoalbuminemia, dyslipidemia, serum electrolyte imbalance, oxidative stress, renal function abnormities, and kidney pathological lesions. Anti-inflammatory cytokine IL-10 expression was elevated after CTX administration in ADR nephropathy model. CTX inhibited the phosphorylation of IκB-αand NF-κB p65 nuclear translocation. Meanwhile, CTX upregulated the protein level of podocyte-specific nephrin and downregulated the level of fibrosis-related TGF-β. These findings suggest that CTX may be a potential drug for chronic kidney diseases.

وصف الملف: text/xhtml

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fe3092847547093a9f6f5884010e54e1Test
http://europepmc.org/articles/PMC4658410Test

المؤلفون: Zheng-Hong Qin, X.-Y. Zhao, C. Wei, Ai-Ping Qin, J. Liu, Li-Zhi Hong, Chun-Feng Liu, Min Xu, Hui Ling Zhang

المصدر: Neuroscience. 176:381-395

مصطلحات موضوعية: Male, medicine.medical_specialty, Blotting, Western, Ischemia, Peroxisome proliferator-activated receptor, Neuroprotection, Rats, Sprague-Dawley, Brain ischemia, chemistry.chemical_compound, Internal medicine, medicine, Animals, Neurons, chemistry.chemical_classification, Pioglitazone, Reverse Transcriptase Polymerase Chain Reaction, business.industry, General Neuroscience, NF-kappa B, Brain, Infarction, Middle Cerebral Artery, NF-κB, Recovery of Function, medicine.disease, Immunohistochemistry, Rats, PPAR gamma, Disease Models, Animal, IκBα, Neuroprotective Agents, Endocrinology, chemistry, Thiazolidinediones, Apoptotic signaling pathway, business, Reperfusion injury, Signal Transduction

الوصف: Previous studies have demonstrated that pioglitazone (Piog), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. Piog has also been shown to exert anti-inflammatory effects by attenuation of nuclear factor-κB (NF-κB) activation after myocardial ischemia/reperfusion injury. Because NF-κB is known to play a major role in the pathophysiology of brain ischemia, the present study was undertaken to elucidate whether pioglitazone attenuates ischemic neuronal damage through PPARγ-mediated suppression of NF-κB apoptotic signaling pathway. Permanent middle cerebral artery occlusion (pMCAO) model was induced by using an intraluminal filament technique in rats. Piog was administrated i.p. twice (24 h before and at the time of ischemia insult) or once (10 min after ischemia). The neuroprotection of Piog was analyzed by assessing neurological deficits, infarction volume and morphological changes. The inhibition of NF-κB signaling pathway by Piog was evaluated by detecting the nuclear translocation of NF-κB p65 with immunohistochemistry and its target gene p53 by real-time PCR, and the expression of phospholated NF-κB p65 (p- NF-κB p65) in primary cultured neurons and the protein levels of IκBα and p-ERK in the ischemic cortex or striatum with Western blotting analysis. The contribution of a PPARγ mechanism to Piog's inhibitory effects on NF-κB and neuroprotection was evaluated by pretreatment with the PPARγ irreversible antagonist GW9662. In vitro ischemia in cultured primary neurons was induced by the oxygen-glucose deprivation (OGD) and the protective effect of Piog on cultured neurons was measured by lactate dehydrogenase (LDH) assay. Piog (0.5, 1, 2 mg/kg) reduced infarction volume, and improved morphological changes and motor deficits. Piog markedly up-regulated the protein levels of IκBα or p-ERK 6 h or 12 h after ischemia. Piog reduced the nuclear translocation of NF-κB p65 in the ischemic cortical cells and repressed the expression of p53 12 h after ischemia. Pre-treatment with GW9662 blocked Piog-elicited reduction in infarction volume, the increase in protein levels of IκBα and p-ERK, the reduction in the nuclear translocation of NF-κB subunit p65 and the repression of p53 mRNA expression. In addition, Piog attenuated the OGD-induced neuronal damage and inhibited the OGD-induced increases in p- NF-κB p65 in neurons. The present findings suggest that Piog's neuroprotection appears to be associated with PPARγ-mediated suppression of NF-κB signaling pathway.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::390273ce907020906502a67d666cde86Test
https://doi.org/10.1016/j.neuroscience.2010.12.029Test

المؤلفون: Zheng-Hong Qin, Zhen-Lun Gu, You-zhu Miao, Hui-Ling Zhang, Xihui Xu, Yinan Hua, Rong Han, Jun-chao Wu

المصدر: Acta Pharmacologica Sinica. 28:1097-1104

مصطلحات موضوعية: Male, medicine.medical_specialty, Ischemia, Prostaglandin, Striatum, Lithium, medicine.disease_cause, Brain Ischemia, Rats, Sprague-Dawley, Brain ischemia, chemistry.chemical_compound, Heat Shock Transcription Factors, Heat shock protein, Internal medicine, Animals, Medicine, Pharmacology (medical), HSP90 Heat-Shock Proteins, Prostaglandin a, Pharmacology, Prostaglandins A, business.industry, General Medicine, medicine.disease, Rats, DNA-Binding Proteins, Disease Models, Animal, Apoptotic Protease-Activating Factor 1, Endocrinology, chemistry, Apoptosis, Anesthesia, Heme Oxygenase (Decyclizing), business, Oxidative stress, Transcription Factors

الوصف: Aim: To investigate the effects of lithium (Li) and prostaglandin A 1 (PGA1) on the expression of heat shock factor 1 (HSF-1), heat shock proteins (HSP), and apoptosis protease activating factor-1 (Apaf-1) induced by permanent focal ischemia in rats. Methods: The rats were pretreated with a subcutaneous (sc) injection of Li for 2 d or a single intracerebral ventricle (icv) administration of PGA 1 for 15 min before ischemic insult, or a combination of Li (sc, 1 mEq/kg, 2 d) and PGA 1 (icv, 15 min prior to ischemic insult). Brain ischemia was induced by the permanent middle cerebral artery occlusion (pMCAO). Twenty-four hours after the occlusion, the expression of HSF-1, HSP, andApaf-1 in the ischemic striatum were examined with Western blot analysis. Results: The expression of HSF-1, heme oxygenase-1 (HO-1), HSP90α, and Apaf-1 were significantly increased, but the expression of HSP90β was significantly decreased 24 h after the pMCAO. PGA1 and Li and their combination significantly enhanced the ischemia-induced elevation in the levels of HSF-1, HO-1, and HSP90α, and recovered HSP90β expression, but decreased Apaf-1 levels in the ischemic striatum. Conclusion: The present study demonstrates that PGA1 and Li have synergistic effects on the enhancement of the expression of HSP, suggesting that the synergistic effects of PGA1 and Li in the rat model of permanent focal cerebral ischemia may be mediated by the enhancement expression of HSP expression and the downregulation of Apaf-1. Our studies suggest that combined PGA1 and Li may have potential clinical value for the treatment of stroke.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0b64fb115bc7e91798bcd942b71056b4Test
https://doi.org/10.1111/j.1745-7254.2007.00624.xTest

المؤلفون: Mei Li, Meiling Sun, Yuan-Yuan Qin, Zheng-Hong Qin, Guanghui Wang, Feng Han, Rui Sheng, Jieyu Chen, Lijuan Cao

المصدر: Neuroscience bulletin. 31(5)

مصطلحات موضوعية: Male, medicine.medical_specialty, Physiology, Ischemia, Oxidative phosphorylation, Pentose phosphate pathway, medicine.disease_cause, Brain Ischemia, Brain ischemia, Pentose Phosphate Pathway, Mice, Downregulation and upregulation, Internal medicine, medicine, Animals, Glycolysis, Cells, Cultured, Neurons, Mice, Inbred ICR, business.industry, General Neuroscience, Brain, Proteins, General Medicine, medicine.disease, Phosphoric Monoester Hydrolases, Up-Regulation, Oxidative Stress, Endocrinology, nervous system, Reperfusion Injury, Original Article, business, Apoptosis Regulatory Proteins, Neuroscience, Reperfusion injury, Oxidative stress, DNA Damage

الوصف: In previous studies, we showed that TP53-induced glycolysis and apoptosis regulator (TIGAR) protects neurons against ischemic brain injury. In the present study, we investigated the developmental changes of TIGAR level in mouse brain and the correlation of TIGAR expression with the vulnerability of neurons to ischemic injury. We found that the TIGAR level was high in the embryonic stage, dropped at birth, partially recovered in the early postnatal period, and then continued to decline to a lower level in early adult and aged mice. The TIGAR expression was higher after ischemia/reperfusion in mouse brain 8 and 12 weeks after birth. Four-week-old mice had smaller infarct volumes, lower neurological scores, and lower mortality rates after ischemia than 8- and 12-week-old mice. TIGAR expression also increased in response to oxygen glucose deprivation (OGD)/reoxygenation insult or H2O2 treatment in cultured primary neurons from different embryonic stages (E16 and E20). The neurons cultured from the early embryonic period had a greater resistance to OGD and oxidative insult. Higher TIGAR levels correlated with higher pentose phosphate pathway activity and less oxidative stress. Older mice and more mature neurons had more severe DNA and mitochondrial damage than younger mice and less mature neurons in response to ischemia/reperfusion or OGD/reoxygenation insult. Supplementation of cultured neurons with nicotinamide adenine dinuclectide phosphate (NADPH) significantly reduced ischemic injury. These results suggest that TIGAR expression changes during development and its expression level may be correlated with the vulnerability of neurons to ischemic injury.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9bc128563ba083b7b01bf989eda4f5d0Test
https://pubmed.ncbi.nlm.nih.gov/26219221Test

المؤلفون: Laurence N. Raymond, Zheng-Hong Qin, Hui-Ling Zhang, Paul F. Reid, Bo-Wen Chen, Rong Han, Zhen-Lun Gu, Zhi-Xing Chen

المصدر: Toxicon. 48:175-182

مصطلحات موضوعية: Atropine, Male, Pain Threshold, medicine.medical_specialty, Narcotic Antagonists, viruses, Analgesic, Mice, Inbred Strains, Muscarinic Antagonists, (+)-Naloxone, Toxicology, Mice, Internal medicine, Crotalid Venoms, Muscarinic acetylcholine receptor, medicine, Animals, Drug Interactions, Injections, Intraventricular, Pain Measurement, Analgesics, Dose-Response Relationship, Drug, Naloxone, business.industry, Crotalus, Crotoxin, Acetylcholine, Analgesics, Opioid, Endocrinology, Nociception, Opioid, Female, Opiate, business, medicine.drug

الوصف: The venom of Crotalus durissus terrificus is reported to have analgesic activity and the administration of Crotoxin (Cro) to cancer patients is reported to reduce the consumption of analgesics. This study investigated the analgesia induced by Cro and the effects of atropine and naloxone on the antinociceptive activity of Cro in mice and rats. The results showed that Cro at 66.5, 44.3 and 29.5microg/kg (ip) exhibited a dose-dependent analgesic action in mice using the hotplate and acetic acid writhing tests. Cro at 44.3microg/kg (ip) had significant analgesic action in the rat tail-flick test. In the mouse acetic acid-writhing test, intracerebral ventricular administration of Cro 0.3microg/kg produced marked analgesic effects. Microinjection of Cro (0.15microg/kg) into the periaqueductal gray area also elicited a robust analgesic action in rat hotplate test. Atropine at 0.5mg/kg (im) or 10mg/kg (ip) or naloxone at 3mg/kg (ip) failed to block the analgesic effects of Cro. These results suggest that Cro has analgesic effects mediated by an action on the central nervous system. The muscarinic and opioid receptors are not involved in the antinociceptive effects of Cro.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ae01c6e5481d3ef1913f3b640d55987aTest
https://doi.org/10.1016/j.toxicon.2006.04.008Test

المؤلفون: Zheng-Hong Qin, Akifumi Kamata, Yasufumi Shirasaki, Kohji Fukunaga, Ying Mei Lu, Feng Han, Norifumi Shioda

المصدر: Cardiovascular therapeutics. 27(1)

مصطلحات موضوعية: MAPK/ERK pathway, Benzylamines, Time Factors, Muscle hypertrophy, Atrial natriuretic peptide, Natriuretic Peptide, Brain, Medicine, Pharmacology (medical), Myocytes, Cardiac, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, Calcimycin, Cells, Cultured, Sulfonamides, biology, Endothelin-1, Kinase, MEK inhibitor, General Medicine, Cell biology, Mitogen-activated protein kinase, cardiovascular system, Cardiology and Cardiovascular Medicine, Atrial Natriuretic Factor, DNA Replication, medicine.medical_specialty, Indazoles, Cardiomegaly, Transfection, Internal medicine, Ca2+/calmodulin-dependent protein kinase, Nitriles, Butadienes, Animals, Calcium Signaling, RNA, Messenger, Rats, Wistar, Protein Kinase Inhibitors, Cell Proliferation, Cell Size, Pharmacology, Ionophores, business.industry, Endothelin 1, Rats, Endocrinology, Animals, Newborn, biology.protein, business, Calcium-Calmodulin-Dependent Protein Kinase Type 2

الوصف: Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) have pivotal roles in endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. We here tested whether a novel CaM antagonist, DY-9760e inhibits ET-1-induced hypertrophy through inhibition of CaMKII and ERK activities. We first confirmed that Ca(2+) oscillation induced by ET-1 treatment elicits transient activation of CaMKII and ERK in cultured cardiomyocytes. DY-9760e treatment with 3 microM totally and partially inhibited the ET-1-induced CaMKII and ERK activation, respectively. The ET-1-induced ERK activation was also partially blocked by a CaMKII inhibitor, KN93. To confirm involvement of CaMKII activity in the ERK activation by ET-1 and A23187, cultured cardiomyocytes were transfected with a constitutively active CaMKII. The transfection with the active CaMKII elicited ERK activation in cultured cardiomyocytes and cotransfection with dominant negative CaMKII eliminated its ERK activation. Consistent with inhibitory actions of DY-9760e on the ET-1-induced CaMKII and ERK activation, induction of hypertrophy-related genes including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was significantly inhibited by DY-9760e treatment. Combination treatment with DY-9760e and U0126, a MEK inhibitor, totally blocked the ET-1-induced ANP and BNP expression. DY-9760e treatment (3 microM) significantly inhibited the ET-1-induced hypertrophy and combination treatment with DY-9760e and U0126 totally blocked the ET-1-induced hypertrophy in cultured cardiomyocytes. These results suggest that DY-9760e elicits antihypertrophic action on ET-1-induced cardiac hypertrophy through inhibition of CaMKII and ERK activation and that CaMKII activity in part mediates ET-1-induced ERK activation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6676ff4be5063086946965cab00d40f9Test
https://pubmed.ncbi.nlm.nih.gov/19207476Test