Physiopathology of Pulmonary Arterial Hypertension: Mechanistic Studies

BACKGROUND

Pulmonary hypertension is a severe disorder defined by an elevated mean pulmonary arterial pressure (mPAP) as >25 mmHg at rest. A classification of the different types of pulmonary hypertension has been established according to shared pathologic and clinical features as well as similar therapeutic options and recently updated. Five major categories have been defined including 1) pulmonary arterial hypertension (PAH), 2) PH owing to left heart diseases, 3) PH owing to lung diseases and/or hypoxia, 4) chronic thromboembolic PH (CTEPH) and 5) PH with unclear multifactorial mechanisms.

PAH commonly defined by an elevated PAP (>25 mmHg at rest) and a normal pulmonary arterial wedge pressure (<15 mmHg), is characterized by a pre-capillary arteriopathy with the presence of vascular remodeling and formation of plexiform lesions, an increased pulmonary vascular resistance (PVR), which may result in right heart failure. PAH may be idiopathic (IPAH), heritable (HPAH) or associated with drug/toxin exposure or other medical conditions including connective tissue diseases, congenital heart diseases, human immunodeficiency virus or portal hypertension. Familial cases were already reported in the early fifties and, in 2000, bone morphogenic protein receptor type 2 gene (BMPR2) was identified as the gene responsible for more than 70% of HPAH and about 20% of IPAH. BMPR2 belongs to a superfamily of growth factor receptors, including bone morphogenic protein (BMPs) and transforming growth factor beta (TGF-β) and consequently controls cellular functions such as proliferation, migration, differentiation or apoptosis. BMPR2 mutations may favor activation of p38MAPK-dependent pro-proliferative pathways, which is also ; a key player in cytokine-induced inflammatory signaling pathways. Although BMPR2 mutation carriers develop PAH 10 years earlier than non-carriers and display more severe hemodynamic changes, only 20% of BMPR2 mutation carriers will further develop PAH. A role of inflammation in the pathogenesis of PAH has been suggested. A predictive role of various cytokines has been recently evidenced in PAH. The investigators have observed elevated C-reactive protein (CRP) circulating levels in PAH and evidenced a predictive role of CRP in PAH. Interestingly, heterozygous null BMPR2 mice failed to develop PAH unless an additional inflammatory insult was applied. More recently, inhibition of leukocyte recruitment has been shown to impair PAH progression in mice with genetic ablation of endothelial BMPR-II. This consequently suggests that inflammation could play the role of a second hit in BMPR2 mutation carriers to further develop PAH.

Besides, lipoprotein-associated phospholipase A2 (Lp-PLA2) also named plasma platelet-activating factor-acetylhydrolase (PAF-AH), is the product of PLA2G7 gene and is an enzyme capable of inactivating platelet-activating factor (PAF), a potent lipid mediator of inflammation and a potent vasoconstrictor, and its analogs. Several studies have evidenced an increase in PAF-AH mass and activity in hypercholesterolemia and coronary heart disease. In a recent meta-analysis including more than 70,000 patients from 32 epidemiologic studies, high circulating PAF-AH levels have been identified as an independent predictive risk factor for cardiovascular events. When over-expressed in rodents, Lp-PLA2 displayed anti-inflammatory properties and reduced atherogenesis, suggesting a potential anti-inflammatory role of Lp-PLA2. Lp-PLA2 polymorphisms have been identified and Lp-PLA2 activity has been strongly associated with genetic variants related to LDL- cholesterol levels. In a preliminary study, the investigators have observed a diminished Lp-PLA2 activity in the plasma of PAH patients, together with low total and LDL-cholesterol levels.

HYPOTHESIS & OBJECTIVES