F1-ATP synthase beta-subunit and cytochrome c transcriptional regulation in right ventricular hemodynamic overload and hypertrophically stimulated cardiocytes

Cardiac hypertrophic growth secondary to hemodynamic pressure overload caus es changes in energy requirements that map involve the transcriptional upre gulation of oxidative phosphorylation genes. Therefore, two representative nuclear-encoded genes, the mitochondrial F-1-ATP synthase beta-subunit (bet a-subunit) and cytochrome c (cyt c), were examined in a feline chronic pulm onary artery banded right ventricular pressure-overload model. In the hyper trophying right ventricle, beta-subunit and cyt c mRNA levels increased aft er two and seven days, during the peak growth response. To examine cardiac transcriptional regulation, neonatal rat cardiac myocytes (cardiocytes) wer e transiently transfected with beta-subunit promoter constructs ranging fro m -1519 nucleotides (nt) upstream of transcription initiation as well as cy t c promoter constructs ranging from - 726 nt. A full-length p1519 beta-sub unit/Luc construct was alpha-adrenergically inducible by 275% (+/-30%) with this activation being mapped to an enhancer region between -1519 to -1480 nt, Smaller constructs containing more proximal promoter elements were not inducible. Additionally, the full-length and enhancer deleted beta-subunit constructs were also inducible in electrically stimulated cardiocytes, sugg esting a different mechanism of activation. Cyt c constructs containing kno wn constitutive elements from -191 to -167 nt and -139 to -84 nt were respo nsible for the majority of the reporter activity of the full-length promote r but were not inducible in the presence of phenylephrine. Hence, we show t hat promoter regions containing elements common in other metabolism-related gene families are active in neonatal rat cardiocytes, Once more, we have i dentified a beta-subunit genomic region responsive to alpha-adrenergic and electrical stimulation. (C) 1999 Academic Press.