Pharmacology of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterised by a sustained increase in pulmonary vascular pressure due to constriction and remodelling of the pulmonary vasculature and associated right ventricular hypertrophy. This ultimately leads to right heart failure and eventually death. Idiopathic and heritable forms of PAH (iPAH and hPAH, respectively) have a mean age at diagnosis of 35 years and a median survival of 2.8 years if untreated. There is a current lack of specific treatments for PAH, many generic medicines are used and those specifically licensed for PAH have limited therapeutic and severe adverse side effects. Following 5 years therapy survival is only between 42%-63% depending on the underlying cause.

Both iPAH and hPAH occur more frequently in females compared to males. The reason(s) for this increased frequency in females is unclear but an understanding of this gender difference would certainly lead to novel therapeutic strategies. My lab is primarily interested in serotonin as well as alterations in oestrogen metabolism which have been linked to increased penetrance in female patients with PAH.

Serotonin and PAH

Serotonin has been firmly linked to the development of PAH. My lab has a long standing interest in the development of serotinergic drugs for the treatment of PAH. We have shown that tryptophan hydroxylase 1 (Tph1; the rate limiting enzyme in the synthesis of serotonin), the serotonin transporter (SERT; responsible for uptake of serotonin into cells) and the 5-HT1B receptor are all involved in the development of PAH, and genetic or pharmacological knockdown of these targets can protect against PAH in animal models.

The serotonin transporter, gender, and 17β-oestradiol in the development of PAH

We are the first to characterize a mouse model where PAH demonstrates female susceptibility. We have shown that only female and not male mice over-expressing the serotonin transporter (SERT+) spontaneously develop PAH. Furthermore, 17β-oestradiol appears to play a key role in the disease process in these mice. At a cellular level, 17β-oestradiol can also upregulate TPH-1, the 5HT1B receptor, and SERT expression in human pulmonary arterial smooth muscle cells (hPASMCs) and induced proliferation of these cells, a process dependent on both a TPH-1 and the 5-HT1B receptor. Our findings establish interactions between the serotonin system and 17β-oestradiol that may contribute to the increased risk of PAH associated with female gender.

Oestrogen metabolism and PAH

CYP1B1 is a P450 enzyme and is highly expressed in the lung catalysing the oxidation of 17β-estradiol to 4-hydroxy oestrogen (4-OHE), 2-OHE and 16α-OHE1. Recently we have shown that CYP1B1 is up-regulated in female SERT+ mice as well as PASMCs derived from iPAH patients. Both CYP1B1 knockout and pharmacological inhibition of CYP1B1 in two distinct models of the condition, chronic hypoxia and the more severe chronic hypoxia plus SUGEN model also confirmed the importance of the enzyme in PAH. We are currently investigating the underlying mechanisms by which CYP1B1 contributes to the development of PAH.

Our future research aims to further elucidate how increased serotinergic and oestrogenic effects contribute to the development of PAH and determine how these interact and influence gender differences in the development of PAH.