Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 293, Issue 5, Pages H2860-H2869Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.01167.2006
Keywords
transforming growth factor-beta; echocardiography; mitogen-activated kinase
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Tranilast attenuates diastolic dysfunction and structural injury in experimental diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 293: H2860-H2869, 2007. First published August 24, 2007; doi:10.1152/ajpheart.01167.2006. - Diastolic dysfunction is an increasingly recognized complication of diabetes that develops in relatively young patients as a result of diabetic cardiomyopathy (DCM). With recent advances in echocardiographic technology now permitting the reliable assessment of diastolic function in the rat, we examined cardiac function and structure in diabetic rodents and assessed the effects of intervening with tranilast, an antifibrotic compound that has been shown to attenuate the actions of transforming growth factor-beta (TGF-beta) in cardiac fibroblasts. We also sought to examine the mechanism whereby tranilast inhibits the actions of TGF-beta. Six-week-old heterozygous (mRen-2) 27 rats were randomized to receive either streptozotocin or citrate buffer and then further randomized to receive either tranilast ( 400 mg (.) kg(-1) (.) day(-1) by twice daily gavage) or vehicle for another 8 wk. Cell signaling was examined in neonatal cardiac fibroblasts. After 8 wk, diabetic rats showed evidence of impaired diastolic function with reduced early-to-late atrial wave ratio and prolonged deceleration time in association with fibrosis, apoptosis, and hypertrophy ( all P < 0.05). Treatment with tranilast prevented the development of diastolic dysfunction and the histopathological features of DCM. While tranilast did not affect Smad phosphorylation, it significantly attenuated TGF-beta-induced p44/42 mitogen-activated protein kinase phosphorylation.
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