Regulation of expression of contractile proteins with cardiac hypertrophy and failure

Abstract

Transitions in sarcomeric a-actin and cardiac myosin heavy chain (MHC) gene expression have been useful as molecular markers for the development of cardiac hypertrophy and failure. In simpler model systems, α-actin expression has been useful in delineating some of the molecular pathways responsible for its induction following growth stimulation in vitro. In this study, we report that the effects of adrenergic agonists on α-actin expression in neonatal cardiocytes is dependent upon the culture conditions. In cardiocytes plated at 5 x 10 4 cells/cm 2, skeletal α-actin mRNA levels represent 47%, 37% or 42% of total sarcomeric α-actin accumulations following administrations of 4 μM norepinephrine (NE), isoproterenol (Iso), or phenylephrine (PE), respectively. Cultured cardiocytes treated with vehicle (ascorbate) only accumulated 19% skeletal α-actin. Under these tissue culture conditions, in contrast to data reported previously, skeletal α-actin expression is regulated by both α- and β-adrenergic agonist stimulation. Furthermore, we present data showing that an endogenous anti-β-MHC transcript is regulated by both pressure-overload- or thyroxine-induced cardiac hypertrophy. Although anti-β-MHC transcripts do not play a major role in regulating β-MHC gene expression, the presence of this antisense transcript is associated with a novel set of β-MHC degradation products. In vitro studies, where oligonucleotides complementary to β-MHC have been introduced into cardiomyoctyes, show that the mRNA levels of β-MHC are decreased by 14-21% within 72 h after addition of the oligonucleotides. This result together with the presence of β-MHC degradation products suggest that endogenous anti-β-MHC transcripts may be involved in a post-transcriptional regulatory mechanism affecting the steady-state levels of β-MHC expression.