Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of primary pulmonary hypertension (PPH). Here we found that PA-SMCs from patients with PPH grow faster than PA-SMCs from controls when stimulated by serotonin or serum and that these effects are due to increased expression of the serotonin transporter (5-HTT), which mediates internalization of indoleamine. In the presence of 5-HTT inhibitors, the growth stimulatory effects of serum and serotonin were markedly reduced and the difference between growth of PA-SMCs from patients and controls was no longer observed. As compared with controls, the expression of 5-HTT was increased in cultured PA-SMCs as well as in platelets and lungs from patients with PPH where it predominated in the media of thickened pulmonary arteries and in onion-bulb lesions. The L-allelic variant of the 5HTT gene promoter, which is associated with 5-HTT overexpression and increased PA-SMC growth, was present in homozygous form in 65% of patients but in only 27% of controls. We conclude that 5-HTT activity plays a key role in the pathogenesis of PA-SMC proliferation in PPH and that a 5HTT polymorphism confers susceptibility to PPH.
Saadia Eddahibi, Marc Humbert, Elie Fadel, Bernadette Raffestin, Michèle Darmon, Frédérique Capron, Gerald Simonneau, Philippe Dartevelle, Michel Hamon, Serge Adnot
Submitter: Marco Catalano | catalano.marco@hsr.it
Psychiatric Genetics Unit, IRCCS H San Raffaele, DSNP, Milan, Italy
Published November 5, 2001
I read with great interest the paper by Eddahibi and colleagues. The study is straightforward, as is the accompanying commentary by Rabinovitch, and the findings are really exciting. However, my experience with the serotonin pathway leads me to consider an alternative, or perhaps supplementary, explanation for some cases of primary pulmonary hyperplasia (PPH).
To my knowledge, the exact pathogenetic basis of PPH remains unclear, and evidence may suggest a possible role of potassium channels (1), since both dexfenfluramine and aminorex (a noradrenergic drug) can lead to PPH. Moreover, the mitogenic effect of serotonin (5-HT) might be mediated by a surface receptor (i.e. 5-HT2A)(2)or a protein phosphorylation and superoxide cascade (3) in different smooth muscle cells (SMCs). These are really touchy issues, as, in case of surface targets, the more active variant of serotonin transporter (5-HTT) should exert a protective effect mediating a higher clearance rate of 5-HT.
Nevertheless, even in case of an intracellular effect of 5-HT, other points deserve further studies, as suggested by Dr. Rabinovitch. Normally, after its uptake and cellular internalization, 5-HT is metabolized mainly by monoamine oxidase A (MAO-A), which is homogeneously distributed in lung (4) and located in the mitochondria of SMCs (5). Interestingly, MAO-A- deficient transgenic mice show alterations of respiratory network maturation (6), and some have suggested that the combination of fenfluramine and phentermine can cause PPH (7).
Thus, given the presence of a functional polymorphism within the promoter of the MAO-A encoding gene, whose alleles exhibit a significant different transcriptional activity (8), I think a combined genetic analysis in PPH patients could be useful. In other words, it is conceivable that 5-HTT is not the only factor responsible and that less active variant of MAO-A (related to reduced levels of enzymatic activity) could play a role in determining higher intracellular levels of 5-HT after its accumulation by 5-HTT, thus allowing the mitogenic response.
REFERENCES
1. Michelakis ED, Weir EK. 2001. Anorectic drugs and pulmonary hypertension from the bedsisde to the bench. Am.J.Med.Sci. 321:292-299.
2. Sharma SK et al. 2001. Sarpogrelate inhibits serotonin-induced proliferation of porcine coronary artery smooth muscle cells: implications for long-term graft patency. Ann.Thor.Surg. 71:1856-1864.
3. Lee SL et al. 2001. H(2)O(2) signals 5-HT-induced ERK MAP kinase activation and mitogenesis of smooth muscle cells. Am.J.Physiol.-Lung Cell.Mol.Physiol. 281:L646-652.
4. Rodriguez MJ et al. 2000. MAO-A and MAO-B localisation in human lung and spleen. Neurobiol. 8:243-248.
5. Elliot J et al. 1989. Metabolism of amines in the isolated perfused mesenteric arterial bed of the rat. Br.J.Pharmacol. 98:507-514.
6. Burnet H et al. 2001. Altered respiratory activity and respiratory regulations in adult monoamine oxidase A-deficient mice. J.Neurosci. 21:5212-5221.
7. Ulus IH et al. 2000. Characterization of phentermine and related compounds as monoamine oxidase (MAO) inhibitors. Biochem.Pharmacol. 59:1611-1621.
8. Deckert J et al. 1999. Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum.Mol.Genet. 8:621-624.