Loss of Bone Morphogenetic Protein Receptor 2 Is Associated with Abnormal DNA Repair in Pulmonary Arterial Hypertension

Abstract

Occlusive vasculopathy with intimal hyperplasia and plexogenic arteriopathy are severe histopathological changes characteristic of pulmonary arterial hypertension (PAH). Although a phenotypic switch in pulmonary endothelial cells (ECs) has been suggested to play a critical role in the formation of occlusive lesions, the pathobiology of this process is poorly understood. The goal of this study was to identify novel molecular mechanisms associated with EC dysfunction and PAH-associated bone morphogenetic protein receptor 2 (BMPR2) deficiency during PAH pathogenesis. A bioinfomatics approach, patient samples, and in vitro experiments were used. By combining a metaanalysis of human idiopathic PAH (iPAH)-associated gene-expression microarrays and a unique gene expression-profiling technique in rat endothelium, our bioinformatics approach revealed a PAH-associated dysregulation of genes involving chromatin organization, DNA metabolism, and repair. Our hypothesis that altered DNA repair and loss of genomic stability play a role in PAH was supported by in vitro assays where pulmonary ECs from patients with iPAH and BMPR2-deficient ECs were highly susceptible to DNA damage. Furthermore, we showed that BMPR2 expression is tightly linked to DNA damage control because excessive DNA damage leads to rapid down-regulation of BMPR2 expression. Moreover, we identified breast cancer 1 (BRCA1) as a novel target for BMPR2 signaling and a novel modulator of pulmonary EC homeostasis. We show here that BMPR2 signaling plays a critical role in the regulation of genomic integrity in pulmonary ECs via genes such as BRCA1. We propose that iPAH-associated EC dysfunction and genomic instability are mediated through BMPR2 deficiency-associated loss of DNA damage control.

miR-223 reverses experimental pulmonary arterial hypertension

“…We provide extensive evidences linking the abnormal expression of miR-223 to already known pathophysiological processes in PAH, including HIF-1␣ activation (2, 32), impaired DNA damage signaling (9,19), and PARP-1 overexpression (23), as well as the proliferation/apoptosis imbalance of PAH-PASMC (37). Thus, our study not only demonstrates the importance of miRNAs especially miR-223 in PAH but also, on the basis of our in vivo data, suggests that it might represent a new therapeutic target for human PAH.…”

“…We and others highlighted the role of DNA damage signaling and PARP-1 activation in PAH lung vascular cells (9,19,23), but the exact mechanism underlying this deregulation remains unknown. In silico analysis using TargetScan 6.2 revealed that PARP-1 is a predicted target of miR-223.…”

“…This remodeling and obstruction of the PAs leads to increases in pulmonary vascular resistance, right ventricular (RV) failure, and death of patients. Despite recent therapeutic advances, most patients exhibit persistently poor exercise capacity and quality of life, with a 3-yr survival rate of 65% (12).Growing evidence underlines the importance of DNA damage in PAH etiology (9,19,23). Indeed, the sustained inflammation, RAGE expression (21), and metabolic stress (30) observed in PAH result in DNA damage-dependent activation of poly(ADP-ribose)polymerase 1 (PARP-1) in PA smooth muscle cells (PASMCs) of PAH patients (23).…”

“…Growing evidence underlines the importance of DNA damage in PAH etiology (9,19,23). Indeed, the sustained inflammation, RAGE expression (21), and metabolic stress (30) observed in PAH result in DNA damage-dependent activation of poly(ADP-ribose)polymerase 1 (PARP-1) in PA smooth muscle cells (PASMCs) of PAH patients (23).…”

Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension

“…Understanding how aberrant molecular signaling causes DNA damage as an early event that initiates vascular remodeling is the subject of ongoing investigation (18). For example, the inflammatory mediator TNF-α (19), and genetic deficiency of BMPR2 or TopBP1 (20,21) can both promote DNA damage and impair endothelial cell proliferation and survival. Recently, we demonstrated that oxidative stress caused by reoxygenation after hypoxia combined with BMPR2 deficiency induced a mitochondrial DNA deletion, elevated caspase-3/7 activity in PAECs, and impaired reversal of pulmonary hypertension (22).…”