Published online before print February 9, 2009, doi: 10.1161/HYPERTENSIONAHA.108.120816
(Hypertension. 2009;53:539.)
© 2009 American Heart Association, Inc.
Original Articles |
Targeted Expression of Receptor-Associated Late Transducer Inhibits Maladaptive Hypertrophy via Blocking Epidermal Growth Factor Receptor Signaling
From the Cardiovascular Research Center (J.C.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass; Department of Cardiology (J.C., F.F.Y., L.Yang, X.-C.Y.), Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; Cardiovascular Research Institute of Wuhan University (D.-F.S., Z.-Y.B., L.Yan, Q.-Z.T., H.L.), Wuhan, China; Department of Cardiology (D.-F.S., Z.-Y.B., L.Yan, Q.-Z.T., H.L.), Renmin Hospital of Wuhan University, Wuhan, China; Department of Nutrition Sciences (Q.Y.), University of Alabama at Birmingham; Gene Expression Laboratory (A.L.), The Salk Institute for Biological Studies, La Jolla, Calif; and Division of Rheumatology (A.K.G.), Northwestern University Feinberg School of Medicine, Chicago, Ill.
Correspondence to Xin-Chun Yang, MD, Department of Cardiology, Beijing Chaoyang Hospital, Affiliate of Capital Medical University, Beijing 100020, China, 8 Baijiazhuang Rd, Beijing 100020, China. E-mail yangxc{at}medmail.com.cn or Hongliang Li, MD, PhD, Cardiovascular Research Institute of Wuhan University and Department of Cardiology, Renmin Hospital of Wuhan University, JieFang Rd 238, Wuhan 430060, China. E-mail lihl@whu.edu.cn
Receptor-associated late transducer (RALT) is a feedback inhibitor of epidermal growth factor receptor signaling. RALT has been shown previously to be induced in the ischemic heart and to promote cardiomyocyte apoptosis in vitro. However, the role of RALT in cardiac hypertrophy remains unclear. We hypothesized that forced expression of RALT in the murine heart would protect the heart against cardiac hypertrophy in vivo. We investigated the effect of cardiac overexpression of rat RALT on cardiac hypertrophy induced by angiotensin II and isoproterenol in RALT transgenic mice and wild-type littermates. The extent of cardiac hypertrophy was assessed by 2D and M-mode echocardiography as well as by molecular and pathological analyses of cardiac samples. Constitutive expression of rat RALT in cardiac myocytes of murine heart attenuated both hypertrophic and inflammatory responses and preserved cardiac function. These beneficial effects were associated with the attenuation of the epidermal growth factor receptor–dependent cascade that was triggered by angiotensin II and isoproterenol stimulation. Additional evidence demonstrated that RALT expression blocked fibrosis in vivo and collagen synthesis in vitro. Therefore, cardiac overexpression of RALT improves cardiac function and inhibits maladaptive hypertrophy, inflammation, and fibrosis through attenuating epidermal growth factor receptor–dependent signaling.
Key Words: RALT • EGFR • ERK1/2 • cardiac hypertrophy • heart failure • fibrosis
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