Lowering asymmetric dimethylarginine levels as a possible therapeutic strategy in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a group of diseases characterized by elevated pulmonary arterial pressure (greater than 20 mm Hg) eventually leading to right heart failure and death if untreated. PAH may be idiopathic and/or familial, induced by toxins and drugs or associated with other disease processes, such as congenital heart failure. The general prevalence of PAH worldwide is estimated at around 5/1,000,000, with women being twice as likely as men to be affected. PAH is a progressive disease characterised by adverse vascular remodelling of pulmonary arteries leading to widespread obliteration of the smaller arteries. This leads to increased resistance to pulmonary blood flow, with initial right ventricular compensation for the raised pulmonary arterial pressures, and consequently heart failure. The non-specific clinical features and the lack of knowledge of the underlying pathology mean that the prognosis is generally poor with a mean survival rate, after diagnosis, of less than 3 years. Currently there is no cure for PAH and therapeutic options include general measures (annual influenza vaccination, aggressive treatment of respiratory tract infections), and medical therapy (oxygen, anticoagulants, diuretics). Endothelin receptor agonists, prostanoids and phosphodiesterase inhibitors are also used in clinical practice together with lung transplantation as the last option for resistant patients. Asymmetric dimethylarginine (ADMA) is an endogenous homologue of L-arginine that competitively inhibits nitric oxide synthases (NOS). In addition to inhibition of NO production, ADMA also “uncouples” NO synthases, which results in production of superoxide radical instead of NO. ADMA is derived from the proteolysis of proteins that are methylated on arginine residues. The major pathway for catabolism of ADMA is hydrolysis to citrulline and methylamines catalysed by the enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1). ADMA is increased in pulmonary arterial hypertension and is associated with unfavourable outcomes; however, currently there are no therapeutic options available to lower ADMA levels.