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The use of fenfluramines can increase the risk of developing pulmonary arterial hypertension (PAH) in humans, but the mechanisms responsible are unresolved. A recent study reported that female mice lacking the gene for tryptophan hydroxylase-1 ( Tph1 (−/−) mice) were protected from PAH caused by chronic dexfenfluramine, suggesting a pivotal role for peripheral serotonin (5-HT) in the disease process. Here we tested two alternative hypotheses which might explain the lack of dexfenfluramine-induced PAH in  Tph1 (−/−) mice. We postulated that: 1)  Tph1 (−/−) mice express lower levels of pulmonary 5-HT transporter (SERT) when compared to wild-type controls, and 2)  Tph1(−/−)  mice display adaptive changes in the expression of non-serotonergic pulmonary genes which are implicated in PAH. SERT was measured using radioligand binding methods, whereas gene expression was measured using microarrays followed by quantitative real time PCR (qRT-PCR). Contrary to our first hypothesis, the number of pulmonary SERT sites was modestly up-regulated in female  Tph1 (−/−) mice. The expression of 51 distinct genes was significantly altered in the lungs of female  Tph1 (−/−) mice. Consistent with our second hypothesis, qRT-PCR confirmed that at least three genes implicated in the pathogenesis of PAH were markedly up-regulated:  Has2 ,  Hapln3  and  Retlna . The finding that female  Tph1 (−/−) mice are protected from dexfenfluramine-induced PAH could be related to compensatory changes in pulmonary gene expression, in addition to reductions in peripheral 5-HT. These observations emphasize the intrinsic limitation of interpreting data from studies conducted in transgenic mice that are not fully characterized.

Altered Gene Expression in Pulmonary Tissue of Tryptophan Hydroxylase-1 Knockout Mice: Implications for Pulmonary Arterial Hypertension