New Mutations and Pathogenesis of Pulmonary Hypertension: Progress and Puzzles in Disease Pathogenesis

Abstract

Pulmonary arterial hypertension (PAH) is a complex multifactorial disease with poor prognosis characterized by functional and structural alterations of the pulmonary circulation causing marked increase in pulmonary vascular resistance, ultimately leading to right heart failure and death. Mutations in the gene encoding BMPRII-a receptor for the TGF-β (transforming growth factor-beta) superfamily-account for over 70% of families with PAH and ≈20% of sporadic cases. In recent years, however, less common or rare mutations in other genes have been identified. This review will consider how these newly discovered PAH genes could help to provide a better understanding of the molecular and cellular bases of the maintenance of the pulmonary vascular integrity, as well as their role in the PAH pathogenesis underlying occlusion of arterioles in the lung. We will also discuss how insights into the genetic contributions of these new PAH-related genes may open up new therapeutic targets for this, currently incurable, cardiopulmonary disorder.

Keywords: arterioles; hypertension, pulmonary; lung; mutation; prognosis.

Figure 1:. Genetic mutations associated with familial pulmonary arterial hypertension (PAH):

(adapted from ).

Figure 2:. The BMP signalling pathway.

BMP ligands can form homo- or heterodimers which signal through a tetrameric set of receptors, comprising two type I and two type II receptors. Binding of BMP dimers to the receptors triggers a phosphorylation cascade that result in phosphorylation of Smad 1/5/8 and players of various non-SMAD pathways to initiate SMAD and non-SMAD signaling cascades. The non-SMAD pathways include signaling by mitogen-activated proteins kinases (MAPKs p38, ERK, and JNK), PI3K/AKT, and small Rho-like GTPases. Phosphorylated Smads are able to form complexes with Smad4 and translocate to the nucleus. (Illustration credit: Ben Smith)

Figure 3:. PAH physiopathology: a puzzle with many missing pieces.

(Illustration credit: Ben Smith)