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Novel Pharmacological Targets for Pulmonary Arterial Hypertension

James R. Klinger

10.1002/cphy.c200015

Source: Volume 11, Issue 4, October 2021

Published online: September 2021

Full Article on Wiley Online Library



Abstract

Pulmonary arterial hypertension (PAH) is a rare disease characterized by an obliterative vasculopathy of the distal pulmonary circulation that results in severe elevation in pulmonary pressure and pulmonary vascular resistance. PAH is a progressive and devastating disease that usually results in right heart failure and death. Currently available medications have only moderate effects and none are curative. Thus, there is a pressing need for new pharmacologic approaches to this disease. In order to meaningfully advance the treatment of PAH, new agents must target the underlying cause of disease induction and progression. This review discusses the extensive work that has been done in the areas of altered glucose metabolism, tyrosine kinase inhibitions, signaling pathways associated with disease causing gene mutations such as the bone morphogenic protein receptor 2, and inflammation and immunomodulation including the effects of mesenchymal stem cells and the extracellular vesicles they secrete. Epigenetic modifications including the roles of micro RNAs, DNA methylation, histone acetylation and transcription factors that modulate pulmonary vascular remodeling are also reviewed. A brief background of each area of interest is provided with emphasis on those components that have potential to be exploited for the treatment of PAH. Significant findings of cell‐based and animal studies and, where available, the results of early clinical trials, are presented to illustrate the potential of these novel therapeutic targets. Current challenges to the development of small peptides and biologicals for the treatment of PAH and direction for future studies are also briefly discussed. © 2021 American Physiological Society. Compr Physiol 11:2297‐2349, 2021.

Figure 1. Figure 1. Characteristic histopathologic findings in patients with idiopathic pulmonary arterial hypertension. (A) Intimal (arrows) and medial (arrow heads) thickening in a pulmonary artery. (B) Concentric “onion skin” intimal thickening with near‐complete occlusion of the vessel lumen. (C) Muscularization of distal, normally nonmuscularized pulmonary artery. (D) The characteristic plexiform lesion (arrow), demonstrating disorganized endothelial proliferation obstructing the vessel lumen. (E) Intravascular thrombus (nonembolic) in a pulmonary artery. (F) Normal pulmonary artery from a patient without pulmonary hypertension. Scale bars = 100 μm except where noted otherwise. (A‐E) Adapted, with permission, from Stacher E, et al., 2012 440. (F) Adapted, with permission, from Humbert M, et al., 2019 196.
Figure 2. Figure 2. Metabolic pathways in proliferating cells. Growth factor‐activated cell surface receptors signal through tyrosine kinases and activate AKT, PI3K to stimulate glucose uptake and flux through the early part of glycolysis. Pyruvate kinase M2 and pyruvate dehydrogenase play key regulatory roles in steering glucose metabolism to Acetyl‐CoA, providing substrate for the TCA cycle and oxidative phosphorylation. Growth stimuli such as tyrosine kinase signaling negatively regulate flux through the late steps of glycolysis and shift glucose metabolism to lactate generation despite the availability of sufficient oxygen (aerobic glycolysis), making glycolytic intermediates available for macromolecular synthesis as well as supporting NADPH production. Enzymes controlling critical steps in key metabolic pathways are shown in blue boxes. Some of these enzymes are candidates as novel therapeutic targets in pulmonary hypertension. See text for further discussion. Adapted, with permission, from Vander Heiden MG, et al., 2009 488.
Figure 3. Figure 3. Change from baseline in mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and 6‐minute walking distance in meters after 16 weeks of treatment with dichloroacetate (DCA) in patients with pulmonary arterial hypertension. Results are stratified by the number of single‐nucleotide polymorphisms in each of the two alleles of the sirtuin 3 and uncoupling protein 2 genes that cause resistance to dichloroacetate. Number of patients per each group shown in parentheses. Adapted, with permission, from Michelakis ED, et al., 2017 308.
Figure 4. Figure 4. General signaling pathways of receptor tyrosine kinases. Ligand (L) binding to the extracellular domain of the tyrosine kinase receptor causes dimerization that results in autophosphorylation and activation of the intracellular kinase domain (K). The ensuing phosphorylation of docking sites on the receptor leads to the recruitment of enzymes such as phosphoinositide 3‐kinase (PI3K), phospholipase Cγ1 (PLCγ1), proto‐oncogene tyrosine‐protein kinase (SRC), and signal transducer and activator of transcription 3 (STAT3) and adaptor molecules (for example, growth factor receptor‐bound protein 2 (GRB2)) and activation of downstream signaling pathways. These include the AKT (also known as PKB), mitogen‐activated protein kinase, Rac and Rho, and Janus kinase (JAK)‐STAT pathways. The signaling pathways regulate a diverse array of processes including transcription, translation, metabolism, cell proliferation, survival, differentiation, and motility. DAG, diacyl glycerol; ERK, extracellular signal‐regulated kinase; Ins(1,4,5)P3, inositol‐1,4,5‐trisphosphate; MEK, mitogen‐activated protein kinase‐ERK kinase; PDK, phosphoinositide‐dependent kinase; PKC, protein kinase C; PtdIns(4,5)P2, phosphatidylinositol‐4,5‐bisphosphate; PtdIns(4,5)P3, phosphatidyl inositol‐3,4,5‐trisphosphate. Adapted, with permission, from Grimminger F, et al., 2010 152. © 2010, Springer Nature.
Figure 5. Figure 5. The BMPR2 signaling pathway illustrating canonical (green) and noncanonical (gray, blue) targets that can be activated. The activation of downstream signaling targets is influenced by the combination of type 1 and type 2 receptors as well as the ligand. ActR, activin receptor; Akt, protein kinase b; ALK, activin‐like receptor; BMP, bone morphogenetic protein; BMPR, Bone Morphogenetic Protein Receptor; BRE, BMP response element; c‐Src, proto‐oncogene tyrosine‐protein kinase Src; CLIC4, chloride intracellular channel 4; Dvl, Disheveled; Erk, extracellular signal‐regulated kinase; FKBP1A, FK binding protein 1A; GSK3‐β, glycogen synthase kinase 3‐β; ID, inhibitor of differentiation; JNK, c‐Jun N‐terminal kinase; LIMK, Lin11, Isl‐1, and Mec‐3 domain kinase; MAPK, mitogen‐activated protein kinase; PI3K, phosphoinositide 3‐kinase; PPARγ, peroxisome proliferator‐activated receptor gamma; Rac1, Ras‐related C3 botulinum toxin substrate 1; RAGE, receptor for advanced glycation end products; RhoA, Ras homolog gene family, member A; SMAD, Mothers against decapentaplegic; SMURF, SMAD‐specific E3 ubiquitin protein ligase; Tak1, transforming growth factor‐β activated kinase 1; VEGFR3, vascular endothelial growth factor receptor 3. Adapted, with permission, from Andruska A and Spiekerkoetter E, 2018 14. Licenced under CC BY 4.0.
Figure 6. Figure 6. BMPR2 mutations associated with PAH. Red bars represent all different mutation categories and the relative occurrence in the exon. Abbreviation: TM region, transmembrane region. Adapted, with permission, from Tielemans B, et al., 2019 466.
Figure 7. Figure 7. Diagram of hematopoiesis. Common myeloid and lymphoid progenitor cells are derived from hematopoietic stem cells. Common myeloid progenitors differentiate into megakaryocytes, erythrocytes, mast cells, and myeloblasts. The latter undergo further differentiation into polymorphonuclear leukocytes and monocytes/macrophages. Common lymphoid progenitors give rise to natural killer cells and lymphocytes. The latter differentiate into T and B cells. Adapted, with permission, from Rad A and Mikael Häggström MD, 2009, Simplified hematopoiesis. Licenced under CC BY SA 3.0.
Figure 8. Figure 8. (A) Right ventricular systolic pressure (RVSP). (B) Right ventricle to left ventricle + septum weight ratio (RV/LV + S) in rats kept under normoxic conditions (Nx) and in rats with pulmonary hypertension induced by treatment with Sugen 5416 followed by 3 weeks of hypoxia (SuHx) that were treated with phosphate‐buffered saline (PBS), mesenchymal stem cell‐derived extracellular vesicles (MSC‐EV), or extracellular vesicles derived from human adventitial fibroblasts (FL‐EV). (C) Diagram of study protocol and timing of treatments. (D‐F) Muscularization of peripheral pulmonary arteries from Nx‐, SuHx‐PBS‐, and SuHx‐MSC‐EV‐treated rats, respectively. Adapted, with permission of the American Thoracic Society. Copyright © 2021 American Thoracic Society. All rights reserved. Klinger JR, et al., 2020 236.
Figure 9. Figure 9. Biological factors and environmental exposures that may increase the risk of developing pulmonary hypertension via epigenetic modifications. Epigenetic mechanisms mainly include DNA methylation via DNA methyltransferase (DNMT) and histone modification. Histone acetylation and deacetylation are regulated by histone acetyltransferase (HAT) and histone deacetylases (HDAC). MicroRNAs can act to downregulate gene expression by inhibiting RNA translation or directly promote degradation of target mRNAs. LncRNAs recruit chromatin modifiers while inducing chromatin remodeling and histone modifications. Adapted, with permission, from Wang Y, et al., 2018 503. Licenced under CC BY 4.0.


Figure 1. Characteristic histopathologic findings in patients with idiopathic pulmonary arterial hypertension. (A) Intimal (arrows) and medial (arrow heads) thickening in a pulmonary artery. (B) Concentric “onion skin” intimal thickening with near‐complete occlusion of the vessel lumen. (C) Muscularization of distal, normally nonmuscularized pulmonary artery. (D) The characteristic plexiform lesion (arrow), demonstrating disorganized endothelial proliferation obstructing the vessel lumen. (E) Intravascular thrombus (nonembolic) in a pulmonary artery. (F) Normal pulmonary artery from a patient without pulmonary hypertension. Scale bars = 100 μm except where noted otherwise. (A‐E) Adapted, with permission, from Stacher E, et al., 2012 440. (F) Adapted, with permission, from Humbert M, et al., 2019 196.


Figure 2. Metabolic pathways in proliferating cells. Growth factor‐activated cell surface receptors signal through tyrosine kinases and activate AKT, PI3K to stimulate glucose uptake and flux through the early part of glycolysis. Pyruvate kinase M2 and pyruvate dehydrogenase play key regulatory roles in steering glucose metabolism to Acetyl‐CoA, providing substrate for the TCA cycle and oxidative phosphorylation. Growth stimuli such as tyrosine kinase signaling negatively regulate flux through the late steps of glycolysis and shift glucose metabolism to lactate generation despite the availability of sufficient oxygen (aerobic glycolysis), making glycolytic intermediates available for macromolecular synthesis as well as supporting NADPH production. Enzymes controlling critical steps in key metabolic pathways are shown in blue boxes. Some of these enzymes are candidates as novel therapeutic targets in pulmonary hypertension. See text for further discussion. Adapted, with permission, from Vander Heiden MG, et al., 2009 488.


Figure 3. Change from baseline in mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and 6‐minute walking distance in meters after 16 weeks of treatment with dichloroacetate (DCA) in patients with pulmonary arterial hypertension. Results are stratified by the number of single‐nucleotide polymorphisms in each of the two alleles of the sirtuin 3 and uncoupling protein 2 genes that cause resistance to dichloroacetate. Number of patients per each group shown in parentheses. Adapted, with permission, from Michelakis ED, et al., 2017 308.


Figure 4. General signaling pathways of receptor tyrosine kinases. Ligand (L) binding to the extracellular domain of the tyrosine kinase receptor causes dimerization that results in autophosphorylation and activation of the intracellular kinase domain (K). The ensuing phosphorylation of docking sites on the receptor leads to the recruitment of enzymes such as phosphoinositide 3‐kinase (PI3K), phospholipase Cγ1 (PLCγ1), proto‐oncogene tyrosine‐protein kinase (SRC), and signal transducer and activator of transcription 3 (STAT3) and adaptor molecules (for example, growth factor receptor‐bound protein 2 (GRB2)) and activation of downstream signaling pathways. These include the AKT (also known as PKB), mitogen‐activated protein kinase, Rac and Rho, and Janus kinase (JAK)‐STAT pathways. The signaling pathways regulate a diverse array of processes including transcription, translation, metabolism, cell proliferation, survival, differentiation, and motility. DAG, diacyl glycerol; ERK, extracellular signal‐regulated kinase; Ins(1,4,5)P3, inositol‐1,4,5‐trisphosphate; MEK, mitogen‐activated protein kinase‐ERK kinase; PDK, phosphoinositide‐dependent kinase; PKC, protein kinase C; PtdIns(4,5)P2, phosphatidylinositol‐4,5‐bisphosphate; PtdIns(4,5)P3, phosphatidyl inositol‐3,4,5‐trisphosphate. Adapted, with permission, from Grimminger F, et al., 2010 152. © 2010, Springer Nature.


Figure 5. The BMPR2 signaling pathway illustrating canonical (green) and noncanonical (gray, blue) targets that can be activated. The activation of downstream signaling targets is influenced by the combination of type 1 and type 2 receptors as well as the ligand. ActR, activin receptor; Akt, protein kinase b; ALK, activin‐like receptor; BMP, bone morphogenetic protein; BMPR, Bone Morphogenetic Protein Receptor; BRE, BMP response element; c‐Src, proto‐oncogene tyrosine‐protein kinase Src; CLIC4, chloride intracellular channel 4; Dvl, Disheveled; Erk, extracellular signal‐regulated kinase; FKBP1A, FK binding protein 1A; GSK3‐β, glycogen synthase kinase 3‐β; ID, inhibitor of differentiation; JNK, c‐Jun N‐terminal kinase; LIMK, Lin11, Isl‐1, and Mec‐3 domain kinase; MAPK, mitogen‐activated protein kinase; PI3K, phosphoinositide 3‐kinase; PPARγ, peroxisome proliferator‐activated receptor gamma; Rac1, Ras‐related C3 botulinum toxin substrate 1; RAGE, receptor for advanced glycation end products; RhoA, Ras homolog gene family, member A; SMAD, Mothers against decapentaplegic; SMURF, SMAD‐specific E3 ubiquitin protein ligase; Tak1, transforming growth factor‐β activated kinase 1; VEGFR3, vascular endothelial growth factor receptor 3. Adapted, with permission, from Andruska A and Spiekerkoetter E, 2018 14. Licenced under CC BY 4.0.


Figure 6. BMPR2 mutations associated with PAH. Red bars represent all different mutation categories and the relative occurrence in the exon. Abbreviation: TM region, transmembrane region. Adapted, with permission, from Tielemans B, et al., 2019 466.


Figure 7. Diagram of hematopoiesis. Common myeloid and lymphoid progenitor cells are derived from hematopoietic stem cells. Common myeloid progenitors differentiate into megakaryocytes, erythrocytes, mast cells, and myeloblasts. The latter undergo further differentiation into polymorphonuclear leukocytes and monocytes/macrophages. Common lymphoid progenitors give rise to natural killer cells and lymphocytes. The latter differentiate into T and B cells. Adapted, with permission, from Rad A and Mikael Häggström MD, 2009, Simplified hematopoiesis. Licenced under CC BY SA 3.0.


Figure 8. (A) Right ventricular systolic pressure (RVSP). (B) Right ventricle to left ventricle + septum weight ratio (RV/LV + S) in rats kept under normoxic conditions (Nx) and in rats with pulmonary hypertension induced by treatment with Sugen 5416 followed by 3 weeks of hypoxia (SuHx) that were treated with phosphate‐buffered saline (PBS), mesenchymal stem cell‐derived extracellular vesicles (MSC‐EV), or extracellular vesicles derived from human adventitial fibroblasts (FL‐EV). (C) Diagram of study protocol and timing of treatments. (D‐F) Muscularization of peripheral pulmonary arteries from Nx‐, SuHx‐PBS‐, and SuHx‐MSC‐EV‐treated rats, respectively. Adapted, with permission of the American Thoracic Society. Copyright © 2021 American Thoracic Society. All rights reserved. Klinger JR, et al., 2020 236.


Figure 9. Biological factors and environmental exposures that may increase the risk of developing pulmonary hypertension via epigenetic modifications. Epigenetic mechanisms mainly include DNA methylation via DNA methyltransferase (DNMT) and histone modification. Histone acetylation and deacetylation are regulated by histone acetyltransferase (HAT) and histone deacetylases (HDAC). MicroRNAs can act to downregulate gene expression by inhibiting RNA translation or directly promote degradation of target mRNAs. LncRNAs recruit chromatin modifiers while inducing chromatin remodeling and histone modifications. Adapted, with permission, from Wang Y, et al., 2018 503. Licenced under CC BY 4.0.
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Article Title: Novel Pharmacological Targets for Pulmonary Arterial Hypertension
 

How to Cite

James R. Klinger. Novel Pharmacological Targets for Pulmonary Arterial Hypertension. Compr Physiol 2021, 11: 2297-2349. doi: 10.1002/cphy.c200015