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(Circulation. 2005;111:782-790.)
© 2005 American Heart Association, Inc.

Hypertension

Retinoids and Pulmonary Hypertension

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.).

Correspondence to Dr Yuichiro J. Suzuki, Department of Pharmacology, Georgetown University Medical Center, NW403 Medical–Dental Bldg, 3900 Reservoir Rd NW, Washington, DC 20057. E-mail ys82{at}georgetown.edu

Received July 17, 2004; revision received October 2, 2004; accepted November 4, 2004.

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, RARß, RAR, RXR, and RXRß. 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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