Endothelial-Like Progenitor Cells Engineered to Produce Prostacyclin Rescue Monocrotaline-Induced Pulmonary Arterial Hypertension and Provide Right Ventricle Benefits

Abstract

P ulmonary arterial hypertension (PAH) is a progressive disorder characterized by abnormally high blood pressure in the pulmonary artery, right ventricular (RV) overload, and, eventually, right heart failure leading to death. The estimated median survival of patients diagnosed with idiopathic PAH is <3 years. 1 The only treatment option that has been shown to increase the survival rate is the continuous systemic administration of prostacyclin 2 ; the median survival rate increases from 2.8 years in untreated patients to 5 years in treated patients. 3,4 However, systemic prostacyclin therapy has serious limitations, including a short halflife and the need for a permanent intravenous catheter. Other treatment options are needed. One alternative being studied is cell-based gene therapy using bone marrow-derived endothelial-like progenitor cells (ELPCs) that express endothelial nitric oxide synthase (eNOS). 5 However, unlike synthetic prostacyclin and its analogs, eNOS treatment is not an established therapeutic approach and has not been included in the PAH treatment algorithm used by clinicians. 2 In the present study, we hypothesize that prostacyclin-producing ELPCs, delivered via the jugular vein, may provide sustained therapeutic effects without the limitations associated with systemic delivery of prostacyclin. Because prostacyclin is produced from arachidonic acid in a serial fashion by the enzymes cyclooxygenase (COX) and prostacyclin synthase (PGIS), we have generated a nonviral vector expressing a human COX isoform 1-PGIS fusion protein. 6 The fusion enzyme is anchored across the membrane of the endoplasmic Background-Intravenous prostacyclin is approved for treating pulmonary arterial hypertension (PAH), but it has a short half-life and must be delivered systemically via an indwelling intravenous catheter. We hypothesize that localized jugular vein delivery of prostacyclin-producing cells may provide sustained therapeutic effects without the limitations of systemic delivery. Methods and Results-We generated a vector expressing a human cyclooxygenase isoform 1 and prostacyclin synthase fusion protein that produces prostacyclin from arachidonic acid. Endothelial-like progenitor cells (ELPCs) were transfected with the cyclooxygenase isoform 1-prostacyclin synthase plasmid and labeled with lentivirus expressing nuclear-localized red fluorescent protein (nuRFP). The engineered ELPCs (expressing cyclooxygenase isoform 1-prostacyclin synthase and nuRFP) were tested in rats with monocrotaline (MCT)-induced PAH. In PAH prevention studies, treatment with engineered ELPCs or control ELPCs (expressing nuRFP alone) attenuated MCT-induced right ventricular systolic pressure increase, right ventricular hypertrophy, and pulmonary vessel wall thickening. Engineered ELPCs were more effective than control ELPCs in all variables evaluated. In PAH reversal studies, engineered ELPCs or control ELPCs increased the survival rate of rats with established PAH and decreased right ventricular hypertrophy. Engineered ELPCs provided ...

Metabolomic analysis revealed the role of DNA methylation in the balance of arachidonic acid metabolism and endothelial activation

“…Another study demonstrated that altered CYP levels contributed to vascular and tubular abnormalities in renal disease [22]. Accumulating evidence suggests that the expression of enzymes involved in AA metabolism is related to the progression of many diseases, such as pulmonary artery hypertension and inflammation [23,24]. Given that balanced levels of AA metabolites regulate cell function and disease condition, changes in the level of specific AA metabolites may reflect systematic responses to stimulation.…”

Targeted Delivery of Pulmonary Arterial Endothelial Cells Overexpressing Interleukin-8 Receptors Attenuates Monocrotaline-Induced Pulmonary Vascular Remodeling

“…autologous or heterologous transplantation), 5) age of cells, and most importantly, 6) targeting delivery of cells to damaged organs to maximize therapeutic effects. Several strategies including growth factor delivery (15,17), gene therapy (14,18,19) and stem cell therapy (16,17) have been developed to promote vascular repair in pulmonary vascular diseases. Among them, cell-based therapy has emerged as the most promising therapeutic tool for treatment of pulmonary hypertension.…”

“…Both non-selective bone marrow-derived stem cells (MSCs) and selective endothelial progenitor cells (EPCs) have been used in rodent models of hypoxia- or MCT-induced pulmonary arterial remodeling and hypertension (11,14–17). Intra-tracheal administration of MSCs has been shown to attenuate neonatal hyperoxia-induced lung injury (16).…”

“…Localized jugular vein delivery of prostacyclin-producing EPCs attenuates MCT-induced RV systolic pressure increase, RV hypertrophy, and pulmonary vessel wall thickening. These effects have led to functional recovery of pulmonary arteries (17). …”

Pathways and Drugs in Pulmonary Arterial Hypertension – Focus on the Role of Endothelin Receptor Antagonists

“…Methods of delivery, and the adverse effect profile of the currently available PAH-specific drugs create further management difficulties. Nanoparticle-mediated drug delivery systems, including solid lipid nanoparticles, polymeric nanoparticles and liposomes [65,66], along with the use of stem cells/ progenitor cells as a vehicle for endothelial vasodilatory agents, such as prostacyclin-producing cells [67], are currently under investigation. These will open new perspectives in PAH treatment by modifying the problematic physical properties of currently available drugs, for example increasing drug solubility, encapsulation efficacy and surface changes to improve drug release and maximizing the effect.…”