Pathological Mechanisms and Potential Therapeutic Targets of Pulmonary Arterial Hypertension: A Review

Abstract

Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease characterized by pulmonary vasculature reconstruction and right ventricular dysfunction. The mortality rate of PAH remains high, although multiple therapeutic strategies have been implemented in clinical practice. These drugs mainly target the endothelin-1, prostacyclin and nitric oxide pathways. Management for PAH treatment includes improving symptoms, enhancing quality of life, and extending survival rate. Existing drugs developed to treat the disease have resulted in enormous economic and healthcare liabilities. The estimated cost for advanced PAH has exceeded $200,000 per year. The pathogenesis of PAH is associated with numerous molecular processes. It mainly includes germline mutation, inflammation, dysfunction of pulmonary arterial endothelial cells, epigenetic modifications, DNA damage, metabolic dysfunction, sex hormone imbalance, and oxidative stress, among others. Findings based on the pathobiology of PAH may have promising therapeutic outcomes. Hence, faced with the challenges of increasing healthcare demands, in this review, we attempted to explore the pathological mechanisms and alternative therapeutic targets, including other auxiliary devices or interventional therapies, in PAH. The article will discuss the potential therapies of PAH in detail, which may require further investigation before implementation.

Keywords: hemodynamics; pulmonary arterial hypertension; right ventricular dysfunction; therapy advances.

Figure 1.

Activation of BMP signaling with or without mutated BMPR2 and the pharmacological mechanism of FK506. BMP signaling in the presence of normal or mutated dysfunctional BMPR2. Mutated BMPR2 protein disturbs the dissociation of FKBP12-calcineurin from BMPR1 when stimulated by activating doses of BMPs. FK506 binds to FKBP12 and promotes the dissociation of FKBP12-calcineurin from BMPR type 1 receptors and then activates the downstream signaling pathway. BMP: bone morphogenetic protein; FKBP12: FK506-binding protein 12.

Figure 2.

Pathobiology of PAH and potential therapeutic targets. Pathological mechanisms and potential therapeutic targets of PAH. The pulmonary artery wall consists of three structural layers, including the adventitia, media, and intima. Various pathogenic factors, such as gene mutations, drugs/poisons, and hypoxia, can induce pulmonary arteriole vascular vasoconstriction, characterized by luminal stenosis, endothelial dysfunction, inflammation, infiltration, etc., ultimately causing RHF. The endothelin-1, prostacyclin, and nitric oxide pathways have been targeted in clinical practice and are three pivotal pathways approved in PAH management. Potential therapeutic targets are emerging as the pathobiology of PAH is revealed. AS: atrial septostomy; BAS: balloon atrial septostomy; PADN: pulmonary artery denervation; ECMO: extracorporeal membrane oxygenation.