Exploring New Therapeutic Pathways in Pulmonary Hypertension. Metabolism, Proliferation, and Personalized Medicine

Abstract

In this review, we explore the main themes from the 62nd Annual Aspen Lung Conference (hypoxia, cellular metabolism, inflammatory pathways, aberrant proliferation, and personalized medicine) and highlight challenges and opportunities in the coming decade of pulmonary vascular disease.

Keywords: cellular proliferation; hypoxia signaling; personalized medicine; pulmonary hypertension.

Figure 1.

These were the main themes in the field of pulmonary hypertension discussed in the 62nd Thomas L. Petty Aspen Lung Conference, “Exploring New Therapeutic Pathways in Pulmonary Hypertension.” BMPR2 = bone morphogenetic protein receptor type 2; FOXO = forkhead box O.

Figure 2.

(A) In a normoxic environment, HIF-1α interacts with PHD and is ubiquitinated and targeted for degradation. In a hypoxic environment, HIF-1α and HIF-1β target to the nucleus, recruit coactivators CBP and p300, and lead to transcription of an HRE domain. CBP = CREB-binding protein; HIF = hypoxia inducible factor; HRE = hypoxia response element; p300 = EP300 or E1A binding protein; PHD = prolyl hydroxylase domain; Ub = ubiquitous; VHL = Von Hippel Lindau protein. Reprinted from Reference . (B) Increased HIF-1 levels in PAEC leads to increased glycolysis and SDF-1a, which recruits immune cells. Increased HIF-2 levels increase ET-1 production, promote endothelial-to-mesenchymal transition (EndMT), and lead to increased Arg 2, leading to reduced NO production. ET-1 then stimulates PASMC in a paracrine manner to produce HIF-1 and leads to mitochondrial metabolic changes, vasoconstriction, and proproliferative effects. Increased HIF-1 and HIF-2 in fibroblasts can lead to growth factors that act on both PAECs and PASMCs. Arg 2 = arginase 2; ET-1 = endothelin-1; NO = nitric oxide; PAEC = pulmonary artery endothelial cell; PASMC = pulmonary artery smooth muscle cell; SDF-1α = stromal-derived factor 1α. Reprinted by permission from Reference .

Figure 3.

(A) In normal cells in the presence of oxygen, the predominant metabolism is that of oxidative phosphorylation, to yield 36 mol ATP per mol glucose. In a hypoxic environment, the cell shifts to anaerobic glycolysis, yielding 2 mol ATP per mol glucose. Proliferative cells (e.g., cancer cells) have an ability to undergo aerobic glycolysis, whereby they generate 4 mol ATP per mol glucose, but additional products (acetyl coenzyme A and nicotinamide adenine dinucleotide phosphate) are needed to generate biomass in proliferating cells. Reprinted by permission from Reference . (B) In the setting of energy, nutrient, and metabolic signals, the mTOR substrate complex and Beclin class III PI3K complex lead to formation of the autophagosome. Reprinted by permission from Reference .

Figure 4.

In the appropriate host, with appropriate stimuli (e.g., hypoxia, drugs, shear stress, or virus), pulmonary vascular remodeling occurs in the setting of immune cell infiltration and tertiary lymphoid follicle formation. Immunologic effects include cell-mediated and innate immune responses, contributing to pulmonary vascular remodeling. NK = natural killer; PH = pulmonary hypertension; SMC = smooth muscle cell. Reprinted by permission from Reference .

Figure 5.

(A) There are shared pathways of cellular proliferation in tumorigenesis and pulmonary vascular disease, leading to sustained proliferative signaling, evasion of growth suppressors, apoptosis resistance, limitless replicative potential, and genome instability and mutation. 53BP1 = p53-binding protein 1; AKT = v-akt murine thymoma viral oncogene homolog; ARC = apoptosis repressor with caspase recruitment domain; Bax = Bcl-2–associated X protein; Bim = Bcl-2–interacting mediator of cell death; Chr. = chromosome; EGF = epidermal growth factor; EGFR = EGF receptor; FGF-2 = fibroblast growth factor 2; FGFR = FGF receptor; γ-H2AX = histone H2A variant H2AX phosphorylated at Ser-139; HIPPO = MAPK = mitogen-activated protein kinase; p21WAF1 = cyclin-dependent kinase inhibitor 1A; p27KIP1 = cyclin-dependent kinase inhibitor 1B; p53 = tumor protein 53; PARP-1 = poly(ADP-ribose) polymerase 1; PTEN = phosphatase and tensin homolog; RB = retinoblastoma; Stat3 = signal transducer and activator of transcription 3; TERT = telomerase reverse transcriptase; TGF-β1 = transforming growth factor-β1; VEGF = vascular endothelial growth factor. (B) Molecular pathway cross-talk illustrates the challenge of interfering with signaling pathways at the receptor level and perhaps highlights the concept of targeting downstream cell signaling hubs and transcription factors that lead to proproliferative, prosurvival signaling. Reprinted from Reference . 4EBP1 = 4R-binding protein 1; AC = adenylyl cyclase; BMPR = bone morphogenetic protein receptor; CREB = cyclic AMP–responsive element binding protein; eNOS = endothelial nitric oxide synthase; ERK = extracellular signal–regulated kinase; GPCR = G protein–coupled receptor; GSK3β = GSK 3β; HES = hairy/enhancer of split; ICD = intracellular domain; ILK = integrin-linked kinase; JAK = Janus kinase; MEK = mitogen-activated protein kinase kinase; mTORC1 = mTOR complex 1; mTORC2 = mTOR complex 2; MyoD = myogenic differentiation 1; PKA = protein kinase A; RAF = rapidly accelerated fibrosarcoma; RAS = rat sarcoma; RTK = receptor tyrosine kinase; S6K1 = p70 S6 kinase 1; STAT3 = signal transducer and activator of transcription 3; TF = transcription factor; TGF-βR = TGF-β receptor; TNFR = TNF receptor.

Figure 6.

Approach to develop personalized treatments for patients with pulmonary vascular disease (PVD). Reprinted from Reference .

Figure 7.

Rather than distinct categories, the themes of the 62nd Aspen Lung Conference of genetic/epigenetic signaling, cellular metabolism, and inflammation are intertwined and drive cellular proliferation.

Figure 8.

Three major pathways appear to dominate current thinking: cellular proliferation and extracellular matrix deposition, glycolytic–anaplerotic metabolism, and inflammation. Within this context, a number of pathways are dysregulated based on downregulation to upregulation: NO to ROS and ET1, PHD2 to HIF-2α; BMPR2 to TGFβ; AMPK to TSC,Yap-Taz,mTORC; P53 to FoxO1, FoxM1 and BMPR2 to GMCSF/TNF α/IL-6/IL-1β. EC = extracellular.