MAO-A promoter polymorphism and idiopathic pulmonary arterial hypertension

Abstract

Monoamine oxidases (MAO) are mitochondrial enzymes that convert biogenic amines to their corresponding aldehydes. Two isoforms, MAO-A and MAO-B, exist which differ in their substrate affinities, inhibitor sensitivities and are coded for different genes residing on the X chromosome (Xp11.23). Serotonin is metabolized first in the liver and later in lungs by the enzyme MAO-A, via oxidative deamination. A variable number of tandem repeat (VNTR) polymorphism of 30-bp-repeat sequence present as 3, 3.5, 4, or 5 copies in the promoter region of the monoamine oxidase-A (MAOA) gene and are associated with its transcriptional activity (Sabol et al. 1998). The four-repeat pVNTR yields higher expression levels of a reporter gene than three repeats, in vitro. The MAOA-VNTR polymorphism has been mainly associated with neurological disorders such as panic disorder, anorexia nervosa etc. (Urwin et al. 2003; Guindalini et al. 2005). Increased plasma 5-hydroxytryptamine (5-HT) levels are found in patients with idiopathic pulmonary arterial hypertension (IPAH) (Herve et al. 1995). The longer promoter variant (L) of 5HTT gene transporter, having higher transcriptional activity has been implicated in the pathogenesis of IPAH (Eddahibi et al. 2001). In vitro studies have shown that the ROS generated by the breakdown of 5-HT by MAO-A leads to proliferation of vascular smooth muscle cells (SMC) and cardiac hypertrophy (Bianchi et al. 2005; Coatrieux et al. 2007). DotBlot array of lung specimens from IPAH patients showed an upregulated MAO-A gene activity (Edgar et al. 2006). After its uptake and cellular internalization by the pulmonary artery smooth muscle cells, 5-HT is