Pulmonary arterial hypertension (PAH) is a devastating disorder that can be idiopathic or secondary to a variety of medical conditions, including congenital heart disease, autoimmune disorders, hepatic dysfunction, sickle cell anemia or ingestion of toxins. There are therapies that improve quality of life, but there is no cure short of lung transplantation. Progress in developing new treatments for this condition will depend upon targeting the fundamental mechanisms causing the pulmonary vascular pathology [reviewed in (1)]. Using electron microscopy, we identified fragmentation and loss of elastin as an early feature in the pathogenesis of PAH in patients with congenital heart defects (16). Loss and dysregulation of elastin production are also prevalent in advanced PAH pathology (Figure 1). Utilizing rodent models of PAH, we documented increased activity of a serine elastase expressed by pulmonary arterial (PA) smooth muscle cells (SMCs), which resulted in high turnover and impaired assembly of elastin. This endogenous vascular elastase called 'EVE'could be produced in response to serum or endothelial factors to which SMCs might be exposed under conditions of injury. When the elastase degrades elastic fibers and other components of the extracelluar matrix, growth factors are released in a biologically active form that induce proliferation and migration of PA SMCs. In addition, elastin peptides and other degradation products of the extracellular matrix produced in response to elastase are highly chemoattractant for inflammatory cells (3). Further studies showed that elastase activation of matrix metalloproteinases (MMPs), upregulates tenascin-C, leading to the clustering and activation of growth factor receptors (17) that further promote proliferation of cells eventuating in the formation of a neointlma (2). Moreover, loss of elastin is associated with increased PA stiffness and RV dysfunction. Recently we discovered that 'EVE'is neutrophil elastase (NE) produced by PA SMCs, and that expression of neutrophil elastase (NE) is elevated in PA SMC from PAH patients and from S100A4 over-expressing mice that are prone to develop severe neointimal PA lesions (18, 19) (See Strategy, Figure 10). In addition to being a neutrophil elastase inhibitor, elafin is an anti-viral and antimicrobial agent (20) produced by a variety of cells, including gamma delta T cells (21). It has been studied for its effect on HIV (22) and on pseudomonas aeruginosa (23, 24) and is thought to bind receptors for these pathogens (25). While elastase can be of benefit in restricting pathogen invasion, it does so at the expense of creating a pro-thrombotic state that damages microvessels (26), causing tissue ischemia. This process can be mitigated by inhibiting elastase with elafin since elafin has anti-microbial properties. Further immumomodulatory effects of elafin are related to its action as a proteosome inhibitor that suppresses ubiquitination of kBa and prevents nuclear translocation of NFKB and subsequent activation of inflammatory cytokines (7). Proteosome inhibitors reduce oxidative stress by increasing the transcription factor, Nrf2, and improving superoxide dismutase (S0D1) (antioxidant) production. Proteosome inhibitors can positively influence survival and regeneration of ECs (8, 9) while preventing SMC proliferation (10, 11). In addition to elafin, other factors regulated by the bone morphogenetic protein receptor (BMPR) II signaling pathway protect the PAs against injury. Mutations causing loss of function of BMPRII occur in >70% of patients with familial idiopathic PAH (FPAH) and 25% of those with sporadic idiopathic PAH (IPAH) (27, 28). Moreover reduced expression of BMPRII is observed in IPAH patients without a mutation, and in virtually all patients in whom PAH is associated with other conditions (APAH) (29, 30). The low penetrance of 20% of the BMPRII mutation in causing disease has been addressed by recent genetic studies. It appears that PAH affected vs. non-PAH-affected family members with a BMPRII mutation, have reduced expression of BMPRII from the normal allele (31), or have dysfunction of other members of this signaling pathway such as Smad 8 (32-34), or have polymorphisms causing heightened TGFB1 signaling (35). DNA microarray studies in PAH vs. control lungs documented a reduction in the co-receptor BMPRIA (36) or ligand, BMP4 (37), features that further impede the BMPRII signal. We have shown that signaling via BMPRII induces PPARy dependent regulation of genes such as apolipoprotein E that repress growth factor (PDGF-BB) mediated-signaling and abrogate SMC proliferation (38). Recently we identified a BMP mediated transcription factor complex between PPARy and B catenin, that regulates genes that promote PA EC survival and regeneration. One of these genes, apelin, proved not only to have autocrine effects that recapitulated those of BMPRII ligands in promoting PA EC survival and growth, but also had paracrine properties in suppressing PA SMC proliferation in response to growth factors, and in inducing apoptosis of proliferating PA SMCs (see Figures 7 and 9 in Strategy). Circulating apelin levels are low in patients with PAH (13), and apelin expression is reduced in PA ECs from patients with PAH (see Figure 6 in Strategy). Moreover, replacement of apelin reversed PAH in a transgenic mouse with deletion of PPARy in ECs and low apelin levels (39) (See Figure 14 in Strategy). In addition, apelin is anti-inflammatory(14) and prevents myocardial dysfunction in the rat with monocrotaline induced PAH (15).

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Nicolls, Mark R; Hsu, Joe L; Jiang, Xinguo (2016) Microvascular injury after lung transplantation. Curr Opin Organ Transplant 21:279-84
Maron, Bradley A; Hess, Edward; Maddox, Thomas M et al. (2016) Association of Borderline Pulmonary Hypertension With Mortality and Hospitalization in a Large Patient Cohort: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program. Circulation 133:1240-8
Jiang, X; Nguyen, T T; Tian, W et al. (2015) Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection. Am J Transplant 15:1768-81
Haddad, François; Spruijt, Onno A; Denault, Andre Y et al. (2015) Right Heart Score for Predicting Outcome in Idiopathic, Familial, or Drug- and Toxin-Associated Pulmonary Arterial Hypertension. JACC Cardiovasc Imaging 8:627-38
Spiekerkoetter, Edda; Sung, Yon K; Sudheendra, Deepti et al. (2015) Low-Dose FK506 (Tacrolimus) in End-Stage Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 192:254-7
Hilgendorff, Anne; Parai, Kakoli; Ertsey, Robert et al. (2015) Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice. Am J Physiol Lung Cell Mol Physiol 308:L464-78
Milla, Carlos E; Moss, Richard B (2015) Recent advances in cystic fibrosis. Curr Opin Pediatr 27:317-24
Nickel, Nils P; Spiekerkoetter, Edda; Gu, Mingxia et al. (2015) Elafin Reverses Pulmonary Hypertension via Caveolin-1-Dependent Bone Morphogenetic Protein Signaling. Am J Respir Crit Care Med 191:1273-86
Jiang, Xinguo; Sung, Yon K; Tian, Wen et al. (2014) Graft microvascular disease in solid organ transplantation. J Mol Med (Berl) 92:797-810
Beraud, Anne-Sophie; Guillamet, Cristina Vazquez; Hammes, Jessie L et al. (2014) Efficacy of transthoracic echocardiography for diagnosing heart failure in septic shock. Am J Med Sci 347:295-8

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