Published online before print January 12, 2004, doi: 10.1161/01.CIR.0000105701.98663.D4
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(Circulation. 2004;109:255-261.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice
From the Heart and Stroke Richard Lewar Centre of Excellence (L.L.Y., A.I.G., M.H., D.J.S.); the Departments of Medicine (M.H., D.J.S.) and Laboratory Medicine and Pathobiology (L.L.Y., A.I.G., M.H., D.J.S.), University of Toronto; Cellular and Molecular Biology, Toronto General Hospital (L.L.Y., R.G., M.G.K., A.S., M.H.); and the Terrence Donnelley Heart Center, St Michael’s Hospital (D.J.S.), Toronto, Canada.
Correspondence to Mansoor Husain, Toronto General Hospital, EN 12-221, 200 Elizabeth St, Toronto, Ontario, Canada, M5G 2C4. E-mail mansoor.husain{at}utoronto.ca
Received November 6, 2002; de novo received July 29, 2003; revision received September 11, 2003; accepted September 12, 2003.
Background— Myocardial expression of endothelin-1 (ET-1) and its receptors ETA and ETB is increased in heart failure. However, the role of ET-1 and its signaling pathways in the pathogenesis of myocardial diseases is unclear.
Methods and Results— Human ET-1 cDNA was placed downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA). This line (ET+) was bred with one harboring cardiac myocyte-restricted expression of tTA (
MHC-tTA). Myocardial ET-1 peptide levels were significantly increased in binary transgenic (BT, ET+/tTA+) compared with nonbinary transgenic (NBT, ET+/tTA-; ET-/tTA+; ET-/tTA-) or DOX-treated BT littermates (40.1±4.7 versus 2.6±1.2 fmol/mL, P<0.003). BT mice demonstrated progressive mortality between 5 and 11 weeks after DOX withdrawal, associated with left ventricular dilatation and contractile dysfunction (peak +dP/dT, 4673±468 versus 5585±658 mm Hg/s, P<0.05). An interstitial inflammatory infiltrate, including macrophages and T lymphocytes, was evident in the myocardium of BT mice, associated with sequential increases in nuclear factor-
B translocation and expression of tumor necrosis factor-, interferon-
, interleukin-1 and interleukin-6. Significant prolongation of survival was observed with the combined ETA/ETB antagonist LU420627 (n=8, P<0.05) in BT mice but not the ETA-selective antagonist LU135252 (n=5, P=0.9), consistent with an important role for ETB in this model.
Conclusions— These are the first data to demonstrate that cardiac overexpression of ET-1 is sufficient to cause increased expression of inflammatory cytokines and an inflammatory cardiomyopathy leading to heart failure and death.
Key Words: endothelin • myocarditis • hypertrophy • heart failure
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