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Molecular and Cellular Biology, February 2007, p. 993-1006, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.00996-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Helix-Loop-Helix Protein p8, a Transcriptional Regulator Required for Cardiomyocyte Hypertrophy and Cardiac Fibroblast Matrix Metalloprotease Induction{triangledown} ,{dagger}

Sandro Goruppi,1* Richard D. Patten,1 Thomas Force,2 and John M. Kyriakis1*

Molecular Cardiology Research Institute, Tufts-New England Medical Center, Department of Medicine, Tufts University School of Medicine, 750 Washington Street, Boston, Massachusetts 02111,1 Center for Translational Medicine, Thomas Jefferson University, College Building Suite 316, 1025 Walnut Street, Philadelphia, Pennsylvania 191072

Received 5 June 2006/ Returned for modification 14 August 2006/ Accepted 6 November 2006

Cardiomyocyte hypertrophy and extracellular matrix remodeling, primarily mediated by inflammatory cytokine-stimulated cardiac fibroblasts, are critical cellular events in cardiac pathology. The molecular components governing these processes remain nebulous, and few genes have been linked to both hypertrophy and matrix remodeling. Here we show that p8, a small stress-inducible basic helix-loop-helix protein, is required for endothelin- and {alpha}-adrenergic agonist-induced cardiomyocyte hypertrophy and for tumor necrosis factor-stimulated induction, in cardiac fibroblasts, of matrix metalloproteases (MMPs) 9 and 13—MMPs linked to general inflammation and to adverse ventricular remodeling in heart failure. In a stimulus-dependent manner, p8 associates with chromatin containing c-Jun and with the cardiomyocyte atrial natriuretic factor (anf) promoter and the cardiac fibroblast mmp9 and mmp13 promoters, established activator protein 1 effectors. p8 is also induced strongly in the failing human heart by a process reversed upon therapeutic intervention. Our results identify an unexpectedly broad involvement for p8 in key cellular events linked to cardiomyocyte hypertrophy and cardiac fibroblast MMP production, both of which occur in heart failure.

* Corresponding author. Mailing address: Molecular Cardiology Research Institute, Tufts-New England Medical Center, 750 Washington Street, Box 8486, Boston, MA 02111. Phone: (617) 636-5190. Fax: (617) 636-5204. E-mail for Sandro Goruppi: sgoruppi{at}tufts-nemc.org. E-mail for John M. Kyriakis: jkyriakis{at}tufts-nemc.org.

{triangledown} Published ahead of print on 20 November 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, February 2007, p. 993-1006, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.00996-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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