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Articles by H Aburatani
Total Records ( 2 ) for H Aburatani
  Y Inuzuka , J Okuda , T Kawashima , T Kato , S Niizuma , Y Tamaki , Y Iwanaga , Y Yoshida , R Kosugi , K Watanabe Maeda , Y Machida , S Tsuji , H Aburatani , T Izumi , T Kita and T. Shioi
 

Background— Heart failure is a typical age-associated disease. Although age-related changes of heart are likely to predispose aged people to heart failure, little is known about the molecular mechanism of cardiac aging.

Methods and Results— We analyzed age-associated changes in murine heart and the manner in which suppression of the p110 isoform of phosphoinositide 3-kinase activity modified cardiac aging. Cardiac function declined in old mice associated with the expression of senescence markers. Accumulation of ubiquitinated protein and lipofuscin, as well as comprehensive gene expression profiling, indicated that dysregulation of protein quality control was a characteristic of cardiac aging. Inhibition of phosphoinositide 3-kinase preserved cardiac function and attenuated expression of the senescence markers associated with enhanced autophagy. Suppression of target of rapamycin, a downstream effector of phosphoinositide 3-kinase, also prevented lipofuscin accumulation in the heart.

Conclusions— Suppression of phosphoinositide 3-kinase prevented many age-associated changes in the heart and preserved cardiac function of aged mice.

  Y Kayama , T Minamino , H Toko , M Sakamoto , I Shimizu , H Takahashi , S Okada , K Tateno , J Moriya , M Yokoyama , A Nojima , M Yoshimura , K Egashira , H Aburatani and I. Komuro
 

To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, Alox15 encoding the protein 12/15 lipoxygenase (LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that Alox15 transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in Alox15 transgenic mice with advancing age and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein 1 (MCP-1) was up-regulated in Alox15 transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenoic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells but not in cardiomyocytes. Inhibition of MCP-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in Alox15 transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac MCP-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition.

 
 
 
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