Abstract 3203: Activation of Left Ventricular ErbB Receptors During Pregnancy, and Effects of ErbB Inhibition by Lapatinib
Introduction The neuregulin-ErbB system has emerged as a paracrine cardioprotective system, essential to preserve ventricular performance and myocardial integrity, especially in conditions of pathophysiological cardiac stress. The present study analyzes ventricular ErbB signaling during “physiological” ventricular overload in pregnancy.
Methods and results Sprague Dawley rats (n=36) and C57/BL6 mice (n=42) were studied at different stages of gestation. Echocardiographic assessment confirmed the development of LV dilatation in pregnancy (LV end-diastolic diameter + 10% and LV mass + 30% versus non-pregnant rats, both p<0.01, n=6, without reduction of LV fractional shortening). Western blot analyses of LV tissue revealed a 1.75±0.24 fold increase in expression of NRG-1 protein at early stages of pregnancy as compared to non-pregnant controls (p <0,05, n=6). Receptor activation followed later in pregnancy as demonstrated by increased levels of phosphorylated ErbB2 and ErbB4 (1.94±0.27 and 1.92±0.18 fold respectively at late pregnancy). Total receptor levels remained unchanged. Phosphorylation of ErbB1 (not a NRG-1 receptor but a dimerization partner of ErbB2) increased 2.5 fold ±0.63 at late pregnancy. Downstream ErbB targets Akt-1 and ERK1/2 were also activated. Results were qualitatively similar in rats and mice. Treatment of pregnant mice with lapatinib (80 mg/kg/d by oral gavage throughout pregnancy), an ErbB1/ErbB2 tyrosine kinase inhibitor, inhibited pregnancy-induced ventricular ErbB1/ErbB2 phosphorylation. Lapatinib did not, however, inhibit pregnancy-induced LV dilatation. On the contrary, LV dilatation became slightly more pronounced and at late pregnancy lapatinib induced as slight but reversible decrease in fractional shortening of 6 % (p<0.05, n=7). Lapatinib did not affect active force development of isolated papillary muscles and did not induce myocardial apoptotic cell death.
Conclusion This study is the first to show activation of ventricular ErbB receptors during physiological cardiac adaptations in pregnancy. Pharmacological inhibition of ErbB1 and ErbB2 slightly increased pregnancy-induced LV dilatation, but did not lead to myocardial apoptotic cell death or to reduced cardiac muscle performance.