Transforming growth factor- 1 regulation of C-type natriuretic peptide expression in human vascular smooth muscle cells: dependence on TSC22D1

Mendonça MC, Koles N, Doi SQ, Sellitti DF. Transforming growth factor1 regulation of C-type natriuretic peptide expression in human vascular smooth muscle cells: dependence on TSC22D1. Am J Physiol Heart Circ Physiol 299: H2018–H2027, 2010. First published August 27, 2010; doi:10.1152/ajpheart.00656.2010.—C-type natriuretic peptide (CNP) possesses nitric oxide-like signaling mechanisms and actions in the vasculature, including the inhibition of fibrosis and vascular remodeling through counterregulation of transforming growth factor(TGF) signaling. The leucine zipper protein transforming growth factor stimulated clone 22 domain 1 (TSC22D1), cloned via its presumed binding to a GC-rich element in the CNP promoter, was the first protein to be described as a CNP transcription factor, but the lack of supporting evidence since its discovery and its lack of a classical DNA-binding site have left in question its role in the regulation of CNP by TGFand other factors. To define a specific role for TSC22D1 in CNP transcription, we have examined the effects of the profibrotic growth factors TGF1 and PDGF-BB on CNP mRNA expression in cultured human vascular smooth muscle cells (SMC) in which TSC22D1 expression was suppressed with small interfering RNA. Results showed that TGFand PDGF-BB significantly increased CNP expression in all three SMC types. Twentyfour-hour TGF-induced elevations in CNP were strongly correlated with changes in TSC22D1 mRNA levels, and both genes exhibited their greatest response to TGF1 in coronary artery SMC. Furthermore, siRNA suppression of TSC22D1 expression in coronary artery and aortic SMC by 90% resulted in 45–65% reductions of both PDGFand TGF-stimulated CNP expression, respectively. These results support a postulated role of TSC22D1 as an enhancer of CNP transcription and suggest that TGF-induced upregulation of CNP expression in SMC may be mediated in part by increased transcription of TSC22D1.