Abnormal genes and myocardial fatty acid metabolism in animal with hart dysfunction.

心脏功能障碍动物基因异常与心肌脂肪酸代谢。

• 批准号: 15390364
• 负责人: WATANABE Kenichi
• 金额: $ 7.94万
• 依托单位: Niigata University of Pharmacy and Applied Life Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390364/
• 关键词: heart failure; 14-3-3 protein; cardiac apoptosis; diabetes; hypertrophy; glycogen synthase kinase; drug treatment; angiotensin; 遺伝子治療; 肥満細胞; 心筋細胞; MAPK; p38MAPK; トランスジェニックマウス; シグナル伝達

Dilated cardiomyopathy is a set of heterogeneous diseases of left ventricular dysfunction of unknown etiology, which has a variety of clinical courses and pathological findings. Long-chain fatty acids are one of the major cardiac energy substrates, so understanding long-chain fatty acid metabolism may help in elucidating the mechanisms of various heart diseases. Myocardial long-chain fatty acids metabolism was decreased in rats with heart failure. Although low-dose candesartan can block increases in blood pressure with circulating angiotensin same to the extent as high-close quinapril, it does not confer sufficient protection against injury from the rennin-angiotensin system in heart failure. Carvedilol has beneficial effects and protects cardiac adrenergic neurons in dilated cardiomyopathy.Glycogen synthase kinase (GSK) 3β is a multifunctional protein that positively regulates myocardial apoptosis and negatively regulates hypertrophy. However, the role of GSK3β in the diabetic myocardium is largely unknown. We found that GSK3β became more active (less phosphorylated at serine 9) via decreased Akt phosphorylation, in parallel to JNK activation, which correlated with increased activated caspase 3 and myocardial apoptosis 3 days after streptozotocin (STZ) injection in mice. However, 28 days after STZ injection, GSK3β became inactive, which correlated with the enhanced protein kinase C β2 and p38 MAPK expression, nuclear translocation of nuclear factor of activated T cells c3, cardiac hypertrophy and fibrosis. All of the above parameters were exacerbated in dominant negative 14-3-3 transgenic mice. Our results suggest that GSK3β together with 14-3-3 protein plays essential roles in the signaling of diabetic cardiomyopathy, and treatment with either losartan or tempol prevents these changes.

扩张型心肌病是一组病因不明的异质性左室功能不全疾病，其临床病程和病理表现多种多样。长链脂肪酸是心脏的主要能量底物之一，因此了解长链脂肪酸代谢可能有助于阐明各种心脏疾病的机制。心力衰竭大鼠心肌长链脂肪酸代谢降低。尽管低剂量坎地沙坦可以阻断循环血管紧张素引起的血压升高，其程度与高剂量喹那普利相同，但它不能提供足够的保护，防止心力衰竭时肾素-血管紧张素系统的损伤。卡维地洛对扩张型心肌病的心脏肾上腺素能神经元具有保护作用，糖原合成酶激酶（Glycogen synthase kinase，GSK）3β是一种多功能蛋白，可正性调节心肌细胞凋亡，负性调节心肌肥厚。然而，GSK 3 β在糖尿病心肌中的作用在很大程度上是未知的。我们发现，GSK 3 β通过Akt磷酸化减少而变得更活跃（丝氨酸9处磷酸化减少），与JNK激活平行，这与小鼠链脲佐菌素（STZ）注射后3天激活的caspase 3和心肌细胞凋亡增加相关。而注射STZ后28 d，心肌细胞中GSK 3 β失活，与蛋白激酶C β2和p38 MAPK表达增强、活化T细胞核因子c3核转位、心肌肥厚和纤维化有关。所有上述参数在显性阴性14-3-3转基因小鼠中均加重。我们的研究结果表明，GSK 3 β和14-3-3蛋白在糖尿病心肌病的信号传导中起着重要作用，氯沙坦或tempol治疗可预防这些变化。

项目成果

Comparative Effects of Pranidipine with Amlodipine in Rats with Heart Failure

普拉地平与氨氯地平对心力衰竭大鼠的作用比较

• DOI: 10.1159/000091746
• 发表时间: 2006
• 期刊: Pharmacology
• 影响因子: 3.1
• 作者: P. Veeraveedu;Kenichi Watanabe;Meilei Ma;N. Gurusamy;S. Palaniyandi;J. Wen;Paras Prakash;M. I. I. Wahed;Fadia Kamal;Sayaka Mito;Megumi Kunisaki;M. Kodama;Y. Aizawa
• 通讯作者: Y. Aizawa

Watanabe K et al.: "Comparative effects of perindopril with enalapril in rats with dilated cardiomyopathy."J Cardiovascul Pharmacol.. 42. S105-D109 (2003)

Watanabe K 等人：“培哚普利与依那普利对扩张型心肌病大鼠的比较作用。”J Cardiovascul Pharmacol.. 42. S105-D109 (2003)

Comparative effects of quinapril with enalapril in rats with heart failure.

喹那普利与依那普利对心力衰竭大鼠的影响比较。

• 发表时间: 2004
• 期刊: Pharmacology 71
• 作者: Kenichi Watanabe

Watanabe K et al.: "Immune-mediated myocarditis and interleukin-10 Inflammation and Cardiac Diseases.(Edited by Ciora Z Feuerstein.)"Birkhauser Verlag Basel. Switzerland.. 189-202. (2003)

Watanabe K 等人：“免疫介导的心肌炎和白细胞介素 10 炎症和心脏病。（由 Ciora Z Feuerstein 编辑）”Birkhauser Verlag Basel。

Role of IFN-γ-inducible protein-10 (IP-10/CXCL10) in the progression of pancreatitis-like injury in mice after murine retroviral infection.

IFN-γ诱导蛋白10（IP-10/CXCL10）在小鼠逆转录病毒感染后胰腺炎样损伤进展中的作用。

• 发表时间: 2006
• 期刊: Am J Physiol-Gastr L. (in press)
• 作者: Kawauchi Y;Suzuki K;Watanabe S;Yamagiwa S;Yoneyama H;Han G;Suresh SP;Punniyakoti TV;Watanabe K;Kawachi H;Okada Y;Shimizu F;Asakura H;Aoyagi Y;Narumi S.
• 通讯作者: Narumi S.