Published Online
on February 7, 2005

A more recent version of this article appeared on February 15, 2005

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Submitted on July 17, 2004
Revised on October 2, 2004
Accepted on November 4, 2004

Retinoids and Pulmonary Hypertension

Ioana R. Preston MD, Guangwen Tang PhD, Jason U. Tilan MS, Nicholas S. Hill MD, and Yuichiro J. Suzuki PhD^*

From the Pulmonary, Critical Care and Sleep Division, Tufts-New England Medical Center, Tupper Research Institute (I.R.P., N.S.H., Y.J.S.), and Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University (G.T., J.U.T., Y.J.S.), Boston, Mass; and Department of Pharmacology, Georgetown University Medical Center, Washington, DC (Y.J.S.).

^* To whom correspondence should be addressed. E-mail: ys82{at}georgetown.edu.

Background--Retinoic acid has antimitogenic effects on smooth muscle cells. Studies on the systemic circulation suggest that it may reduce vascular thickening. Relationships between retinoids and pulmonary hypertension/pulmonary vascular remodeling, however, have not been explored. Thus, the present study examined retinoid levels in plasma of patients with idiopathic pulmonary arterial hypertension and the effects of retinoic acid on human pulmonary artery smooth muscle cell growth.

Methods and Results--We measured retinoid levels by gas chromatograph-mass spectrometer technique in plasma of idiopathic pulmonary arterial hypertension patients and in age- and sex-matched healthy control subjects. Patients had significantly lower levels of all-trans retinoic acid and 13-cis retinoic acid than control subjects but similar 9-cis retinoic acid and retinol levels. In cultured human pulmonary artery smooth muscle cells, all-trans retinoic acid suppressed serotonin-induced cell growth. These cells were found to express the retinoid acid receptors RAR, RAR, RAR, RXR, and RXR. Gene array analysis showed that retinoic acid induces the expression of GADD45A, a known cell growth suppressor. Contrary to expectations, plasma from pulmonary hypertension patients suppressed cell growth, likely influenced by factors other than retinoids.

Conclusions--Idiopathic pulmonary arterial hypertension patients have reduced retinoic acid levels, and retinoic acid treatment can elicit growth-inhibitory signals in pulmonary artery smooth muscle cells in vitro. Thus, retinoic acid may influence pulmonary vascular remodeling in humans.

Key words: genes • hypertension, pulmonary • lung • muscle, smooth • remodeling

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