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

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 (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 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.