Role of apoptosis in pulmonary hypertension: From experimental models to clinical trials

Abstract

Pulmonary arterial hypertension (PAH) is a progressive and lethal disease that has a strong female predominance, often affecting the young. Current therapies are mostly vasodilator agents, and while mainly addressing the endothelial dysfunction that has been widely reported in this disease, they may be less effective in treating arterial remodeling. The lung pathology of PAH is characterized by medial hypertrophy and intimal hyperplasia of muscular arteries as well as plexiform lesions, that lead to a widespread narrowing or obliteration of the pulmonary arteriolar bed. However, the pathogenesis of the functional and structural abnormalities of the lung microcirculation in PAH is poorly understood. Perhaps the greatest advancement in the last decade has been the discovery of the “PAH gene,” bone morphogenetic receptor 2 (Bmpr2), however how the loss-of-function mutations in Bmpr2 lead to PAH is unclear. The BMPR2 pathway has recently been shown to mediate survival signaling in endothelial cells (EC), and thus the reduced activity will favor endothelial apoptosis, likely increasing the susceptibility to endothelial injury in response to various environmental triggers. EC apoptosis has been implicated as an initiating event in experimental PAH, leading either directly to the degeneration of pre-capillary arterioles or to the selection of hyperproliferative, apoptosis-resistant ECs that may contribute to “angioproliferative” plexiform lesions. The idea that EC apoptosis may play a central role in the initiation and progression of PAH suggests that therapeutic strategies aimed at endothelial repair and regeneration of ECs may be uniquely effective in the treatment of this disease. Preclinical evaluation and validation on the use of endothelial progenitor cells (EPCs) for the prevention and reversal of experimental PAH is reviewed and the design of a “first in man” clinical trial to assess the safety and efficacy of a combined EPC and endothelial NO-synthase gene therapy for patients that are refractory to standard therapies is discussed.

Introduction

Pulmonary arterial hypertension (PAH) is a disease characterized by elevated pulmonary artery pressures and is associated with significant morbidity and mortality; there is no known cure (Gaine, 2000). Elevated pulmonary vascular resistance results in high right ventricular systolic pressures causing right ventricular remodeling, ultimately progressing to heart failure. On autopsy, the characteristic pathological findings include medial and adventitial remodeling and excessive arterial muscularization (Tuder et al., 2007), as well as the presence of thrombotic lesions (Johnson et al., 2006). In addition, pulmonary arterioles demonstrate intimal lesions, thickening, and fibrosis that is responsible for a decrease in the luminal caliber of these vessels. The most dramatic pathological findings are perhaps the plexiform lesions which often occur distally to an occluded arteriole, usually at branch points and appear to represent an “angioproliferative” process (Archer & Michelakis, 2006). Many investigators believe that these imtimal lesions are the critical pathogical determinants of the severity and progression of this disease, and the overview will focus on the etiology and consequences of endothelial damage in the pathogenesis of PAH.

Pulmonary hypertension can occur in an idiopathic form (IPAH) which was previously known as primary pulmonary hypertension. PAH occasionally occurs in familial form (FPAH). As well, a variety of secondary forms of the disease can be associated (APAH) with other medical conditions such as congenital heart disease with significant left to right shunting (Eisenmenger syndrome) or collagen vascular disorders such as scleroderma. PAH can also arise as a result of HIV infection or the use of anorexigens such as fenfluramine. Although the etiology is likely quite different in these different forms of PAH, they share a nearly identical pathological picture including the presence of the characteristic intimal and plexiform lesions.