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J. Biol. Chem., Vol. 279, Issue 31, 32897-32903, July 30, 2004

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Intron Retention Generates a Novel Id3 Isoform That Inhibits Vascular Lesion Formation^*

Scott T. Forrest, Kurt G. Barringhaus, Demetra Perlegas, Marie-Louise Hammarskjold¶, and Coleen A. McNamara||

From the Cardiovascular Division, Department of Internal Medicine, and the Cardiovascular Research Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908 and Department of Microbiology and the Myles H. Thaler Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908

The expression of intron-containing messages has been shown to occur in a variety of diseases including lactic acidosis, Cowden Syndrome, and several cancers. However, it is unknown whether these intron-containing messages result in protein production in vivo. Indeed, intron-containing RNAs are typically retained in the nucleus, targeted for degradation, or are repressed translationally. Here, we show that during vascular lesion formation in rats, an alternative isoform of the helix-loop-helix transcription factor Id3 (Id3a) generated by intron retention is abundantly expressed. We demonstrate that Id3 is expressed early in lesion formation when the proliferative index of the neointima is highest and that Id3 promotes smooth muscle cell (SMC) proliferation and S-phase entry and inhibits transcription of the cell-cycle inhibitor p21^Cip1. Using an Id3a-specific antibody developed by our laboratory, we show that Id3a protein is induced during vascular lesion formation and that Id3a expression peaks late when the proliferative index is low or declining and extensive apoptosis is observed. Furthermore, Id3a fails to promote SMC growth and S-phase entry or to inhibit p21^Cip1 promoter transactivation. In contrast, Id3a stimulates SMC apoptosis and inhibits endogenous Id3 production. Adenoviral delivery of Id3a inhibited lesion formation in balloon-injured rat carotid arteries in vivo. These data describe a novel feedback loop whereby intron retention generates an Id3 isoform that acts to limit SMC growth during vascular lesion formation, providing the first evidence that regulated intron retention can modulate a pathologic process in vivo.

Received for publication, May 3, 2004

^* This work was supported by National Institutes of Health Grants T32HL007284 (to S. T. F.), T32HLOO7355 (to K. G. B.), RO1 HL062522 and PO1 HL55798 (to C. A. M.), and AI34721, AI054335, and CA097095 (to M.-L. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by the Charles H. Ross Jr. Endowment at the University of Virginia.

^|| To whom correspondence should be addressed. Tel.: 434-982-3366; Fax: 434-924-2828; E-mail: cam8c{at}virginia.edu.

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