Conditional cardiac overexpression of endothelin-1 induces inflammation and dilated cardiomyopathy in mice.
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.


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 (alphaMHC-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-kappaB translocation and expression of tumor necrosis factor-alpha, interferon-gamma, 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.
Yang
Li L
LL
Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Ontario, Canada.
Gros
Robert
R
Kabir
M Golam
MG
Sadi
Almuktafi
A
Gotlieb
Avrum I
AI
Husain
Mansoor
M
Stewart
Duncan J
DJ
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1