Published Online
on January 12, 2004

A more recent version of this article appeared on January 20, 2004

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Submitted on November 6, 2002
Revised on September 11, 2003
Accepted on September 12, 2003

Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice

Li L. Yang MD, MSc, Robert Gros PhD, M. Golam Kabir MD, Almuktafi Sadi MD, PhD, Avrum I. Gotlieb MD, Mansoor Husain MD^*, and Duncan J. Stewart MD

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.

^* To whom correspondence should be addressed. E-mail: mansoor.husain{at}utoronto.ca.

Background--Myocardial expression of endothelin-1 (ET-1) and its receptors ET_A and ET_B 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 ET_A/ET_B antagonist LU420627 (n=8, P<0.05) in BT mice but not the ET_A-selective antagonist LU135252 (n=5, P=0.9), consistent with an important role for ET_B 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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