Tranilast attenuates diastolic dysfunction and structural injury in experimental diabetic cardiomyopathy.
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 x kg(-1) x 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.
Kelly
Darren J
DJ
Department of Medicine, University of Melbourne, St. Vincent's Hospital, Victoria, Australia.
Zhang
Yuan
Y
Connelly
Kim
K
Cox
Alison J
AJ
Martin
Jennifer
J
Krum
Henry
H
Gilbert
Richard E
RE
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D009202:Cardiomyopathies / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D048909:Diabetes Complications / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D003971:Diastole / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D051381:Rats; D013311:Streptozocin; D016896:Treatment Outcome; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D062367:ortho-Aminobenzoates / Q000008:administration & dosage*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D062367:ortho-Aminobenzoates; D013311:Streptozocin; C012293:tranilast