Neuregulin in cardiac hypertrophy in rats with aortic stenosis - Differential expression of erbB2 and erbB4 receptors

Background-Neuregulins are a family of peptide growth factors that promote cell growth and viability. The potential role of neuregulin-erbB signaling in hypertrophic growth and later failure in the adult heart in vivo is not known. Methods and Results-We used ribonuclease protection assays to quantify mRNA levels of neuregulin, erbB2, and erbB4 in left ventricular (LV) tissue and myocytes of normal rats and rats with aortic stenosis with pressure-overlo ad hypertrophy 6 and 22 weeks after banding, At both stages of hypertrophy, Northern blot analyses of mRNA from LV myocytes showed upregulation of atr ial natriuretic peptide, a molecular marker of hypertrophy (P<0.05). LV tis sue neuregulin message levels were similar in animals with aortic stenosis compared with controls (P=NS) and were not detectable in myocytes, LV erbB2 and erbB4 message levels in LV tissue and myocytes were maintained during early compensatory hypertrophy in 6-week aortic stenosis animals compared w ith age-matched controls; in contrast, erbB2 and erbB4 message levels were depressed in 22-week aortic stenosis animals at the stage of early failure (both P<0.01 vs age-matched controls). Immunoblotting of erbB2 and erbB4 al so showed normal protein levels in 6-week aortic stenosis animals compared with controls; however, erbB2 and erbB4 protein levels were depressed in 22 -week aortic stenosis animals (48% decrease in erbB2, P<0.05, and 43% decre ase in erbB4, P<0.01) relative to age-matched controls, Conclusions-The neuregulin receptors erbB2 and erbB4 are downregulated at b oth the message and protein levels at the stage of early failure in animals with chronic hypertrophy secondary to aortic stenosis, These data suggest a role for disabled erbB receptor signaling in the transition from compensa tory hypertrophy to failure.