title: Manipulation of cardiac phosphatidylinositol 3-kinase (PI3K)/Akt signaling by apoptosis regulator through modulating IAP expression (ARIA) regulates cardiomyocyte death during doxorubicin-induced cardiomyopathy.
abstract: PI3K/Akt signaling plays an important role in the regulation of cardiomyocyte death machinery, which can cause stress-induced cardiac dysfunction. Here, we report that apoptosis regulator through modulating IAP expression (ARIA), a recently identified transmembrane protein, regulates the cardiac PI3K/Akt signaling and thus modifies the progression of doxorubicin (DOX)-induced cardiomyopathy. ARIA is highly expressed in the mouse heart relative to other tissues, and it is also expressed in isolated rat cardiomyocytes. The stable expression of ARIA in H9c2 cardiac muscle cells increased the levels of membrane-associated PTEN and subsequently reduced the PI3K/Akt signaling and the downstream phosphorylation of Bad, a proapoptotic BH3-only protein. When challenged with DOX, ARIA-expressing H9c2 cells exhibited enhanced apoptosis, which was reversed by the siRNA-mediated silencing of Bad. ARIA-deficient mice exhibited normal heart morphology and function. However, DOX-induced cardiac dysfunction was significantly ameliorated in conjunction with reduced cardiomyocyte death and cardiac fibrosis in ARIA-deficient mice. Phosphorylation of Akt and Bad was substantially enhanced in the heart of ARIA-deficient mice even after treatment with DOX. Moreover, repressing the PI3K by cardiomyocyte-specific expression of dominant-negative PI3K (p110α) abolished the cardioprotective effects of ARIA deletion. Notably, targeted activation of ARIA in cardiomyocytes but not in endothelial cells reduced the cardiac PI3K/Akt signaling and exacerbated the DOX-induced cardiac dysfunction. These studies, therefore, revealed a previously undescribed mode of manipulating cardiac PI3K/Akt signaling by ARIA, thus identifying ARIA as an attractive new target for the prevention of stress-induced myocardial dysfunction.
authors: From the Department of Cardiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors: Youhei
authors: Y
authors: Kitamura
authors: Masahiro
authors: M
authors: Koide
authors: Yoshiki
authors: Y
authors: Akakabe
authors: Kiyonari
authors: K
authors: Matsuo
authors: Yoshiaki
authors: Y
authors: Shimoda
authors: Yuka
authors: Y
authors: Soma
authors: Takehiro
authors: T
authors: Ogata
authors: Tomomi
authors: T
authors: Ueyama
authors: Satoaki
authors: S
authors: Matoba
authors: Hiroyuki
authors: H
authors: Yamada
authors: Koji
authors: K
authors: Ikeda
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D006706:Homeostasis / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D004317:Doxorubicin; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C587669:Ecscr protein, mouse; C587668:Ecscr protein, rat
keywords: ARIA (Apoptosis Regulator through Modulating IAP Expression); Akt; Apoptosis; Cardiomyocyte Death; Cardiomyopathy; ECSCR (Endothelial Cell Surface-expressed Chemotaxis and Apoptosis Regulator); Heart Failure; PI 3-Kinase (PI3K)