Pulmonary arterial hypertension (PAH) is a fatal disease characterized by impaired regulation of pulmonary hemodynamics and vascular growth;right ventricular failure is the leading cause of death. Our studies have identified loss of pulmonary vascular endothelial nitric oxide synthase (eNOS) activity in PAH, and that the NO deficiency leads to hypoxia-inducible factor-1 (HIF-1) activation, which results in glycolytic, proliferative, apoptosis-resistant endothelial cells that promote vascular remodeling. The mechanism(s) of eNOS activity loss is unknown. eNOS is also present in the cardiomyocyte, where NO synthesis by eNOS is cardioprotective;but eNOS has not been studied in the human PAH heart. Activation of eNOS requires enzyme dephosphorylation at Threonine 495 (T495) and phosphorylation at Serine 1177 (S1177), the latter mediated by cyclic adenosine monophosphate (cAMP)/protein kinase pathways downstream of ?-Adrenergic Receptors (?AR) [Fig 1]. Because ?AR downregulation and desensitization are found in all heart failure, we investigated ?AR in the eNOS activity loss and its consequences on the pulmonary vascular-right ventricular (RV) axis. Explanted human PAH hearts have desensitization and low numbers of ?AR, and for the first time, we show that pulmonary arterial endothelial cells (PAEC) from human PAH lungs have similarly low numbers and de- sensitization of ?AR. Preliminary data reveal that ?AR desensitization is due to deficient dephosphorylation of the receptor by phosphatases, which are inhibited by over-activation of phosphatidyl inositol 3-kinase (PI3Kg). ?AR numbers are low due to defective intracellular recycling of phosphorylated receptors. Consistent with PI3K inhibition of phosphatases, PAH PAEC and cardiomyocytes have high levels of the inactive pT495 eNOS, identifying the cause of decreased NO production upon any type of agonist stimulation, i.e. eNOS is in an inactive state. As in the endothelial cell, NO deficiency in PAH hearts is associated with greater HIF-activation and increased glycolytic metabolism as identified by glycolytic enzyme expression and uptake of the glucose analogue [18F]2-fluoro-2-deoxy-D-glucose by positron emission tomography (fasting FDG-PET) in PAH patients. Exciting preliminary studies indicate that b-blockers reverse ?AR dysfunction, restore phosphatase- mediated eNOS activation, and thus increase cAMP and NO production, respectively. Thus, we hypothesize that cardiomyocytes and endothelial cells in PAH suffer from interconnected abnormalities of ?AR function and eNOS activation that lead to a HIF-mediated maladaptive vascular and cardiomyocyte phenotype, all of which is reversible by ?-blocker. We test this hypothesis PAEC derived from patients'lungs, explanted human hearts, and in a mechanistic longitudinal study of ?AR blockade in PAH patients.
Pulmonary arterial hypertension (PAH) is a fatal disease associated with increased pulmonary artery pressure and abnormalities in blood vessel growth. Heart failure is the primary cause of death, but current therapies focus entirely on treating the pulmonary hypertension. The determinants of heart failure are unknown. Some patients have adaptive responses of the heart and retain good function for years, while others have progressive heart failure. The goal of this study is to discover the fundamental mechanisms underlying the development and progression of heart failure so that we can use the knowledge to develop successful strategies for comprehensive treatment of the pulmonary hypertension and heart failure.
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