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Pulmonary arterial hypertension: New pathophysiological insights and emerging therapeutic targets
International Journal of Biochemistry and Cell Biology 104 (2018) 9–13
Contents lists available at ScienceDirect
International Journal of Biochemistry and Cell Biology journal homepage: www.elsevier.com/locate/biocel
Medicine in focus
Pulmonary arterial hypertension: New pathophysiological insights and emerging therapeutic targets Alice Bourgeoisa, Junichi Omuraa, Karima Habbouta, Sebastien Bonneta, Olivier Boucherata,b, a b
T ⁎
Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada Department of Medicine, Université Laval, Québec, QC, Canada
A R T I C LE I N FO
A B S T R A C T
Keywords: Vascular remodeling Metabolism Epigenetic DNA damage
Pulmonary arterial hypertension (PAH) encompasses a group of clinical entities characterized by sustained vasoconstriction and progressive vascular remodeling that act in concert to elevate pulmonary vascular resistance. The current treatments for PAH are mainly dedicated to target the process of vasoconstriction and do not offer a cure. There is now accumulating evidence that expansion of pulmonary artery cells due to increased proliferation and apoptotic evasion is a key pathological component of vascular remodeling that occurs in PAH. Thus, vascular lesions seen in advanced PAH patients present some cancer-like characteristics offering important avenues for exploration and expanding treatment options. In this review article, we will discuss recent advances into mechanisms underlying disease progression, with a focus on pulmonary artery smooth muscle cells.
1. Introduction
PA vascular cells, including PA smooth muscle cells (PASMCs), adventitial fibroblasts, but also PAECs themselves (Figs. 1 and 2). These alterations lead to a gradual narrowing of the vascular luminal and possibly to complete occlusion. Currently approved drugs for PAH, mainly dedicated to reduce the pulmonary vasomotor tone, do not cure the disease and only confer modest mortality and quality of life benefits (Lajoie et al., 2016). In view of this, the pathogenic paradigm of PAH has gradually shifted away from vasoconstriction towards much greater focus on vascular remodeling with significant research effort directed toward deciphering the molecular mechanisms allowing PA cells (especially PASMCs) to survive and hyper-proliferate, notwithstanding exposure to chronic damaging stresses (Boucherat et al., 2017). Considering that the phenotype of PAH cells in an advanced stage of the disease is quite similar to that observed in cancer cells, this suggests that lessons learned from the field of oncology may provide valuable insights into PAH pathogenesis, and indirectly that drugs currently used in cancer and demonstrating safety profiles could be repurposed to tackle PAH. While inflammation and genetic abnormalities are key factors of PAH pathogenesis, determining the role of DNA damage response, metabolic reprogramming, endothelial-mesenchymal transition and epigenetics have become a major focus in PAH research and substantial effort are directed towards identifying clinical targets.
Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by vasoconstriction and vascular remodeling of distal pulmonary arteries (PAs), resulting in a persistent elevation of the mean PA pressure above 25 mmHg at rest, and ultimately in right heart failure (Lau et al., 2017). PAH is classified into subgroups based on etiology, including idiopathic, heritable (corresponding mostly with heterozygous germline Bone morphogenetic protein receptor-type 2, BMPR2 mutations), drug-induced (e.g. appetite suppressants, methamphetamine, etc.) and associated with other conditions (e.g. scleroderma, HIV, etc.) (Lau et al., 2017). Regardless of their etiology, all forms of PAH exhibit similar pulmonary vascular lesions suggesting shared pathological mechanisms. Mounting evidence supports the concept that development of PAH follows a biphasic pattern; a model supported by studies showing that apoptotic drugs able to reverse advanced PAH (Schermuly et al., 2005), at the expense of severe side effects (Hoeper et al., 2013), also predispose to development of the disease (Guignabert et al., 2016). Indeed, due to genetic predisposition and exposition to numerous insults (e.g. oxidative and shear stresses, inflammation), PA endothelial cell (PAEC) dysfunction is recognized as the primary event that causes PAH. In this model, PAECs that undergo apoptosis liberate a variety of cytokines and growth factors creating conditions that subsequently stimulate vessel constriction along with favoring the emergence of highly proliferative and apoptosis-resistant
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Corresponding author at: Pulmonary Hypertention Research Group, IUCPQ Research Centre, 2725, chemin Sainte-Foy, Québec, QC, G1V 4G5, Canada. E-mail address: [email protected] (O. Boucherat).
https://doi.org/10.1016/j.biocel.2018.08.015 Received 16 April 2018; Received in revised form 24 August 2018; Accepted 29 August 2018 Available online 03 September 2018 1357-2725/ © 2018 Elsevier Ltd. All rights reserved.
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Fig. 1. Schematic progression of pulmonary arterial hypertension. Following endothelial dysfunction, distal pulmonary arteries (PAs) undergo progressive vascular remodeling associated with exaggerated proliferation and resistance to apoptosis of PA resident cells. This structural change progressively results in occlusion of the pulmonary vascular lumen and contributes to elevations of pulmonary vascular resistances (PVR) and PA pressure. As a result of pressure-overload, the right ventricle (RV) initially compensates by an increase in hypertrophy and contractibility to maintain cardiac output (CO). In most of patients, however, these compensatory mechanisms fail and premature death occurs.
2. Pathogenesis 2.1. Immune dysregulation As a result of perivascular accumulation of immune cells (such as macrophages, lymphocytes, dendritic and mast cells), a myriad of proinflammatory mediators have been documented to be increased in PAH patients, collectively contributing to the initiation and progression of vascular remodeling (Kuebler et al., 2018). Among them, the interleukin-6 (IL-6) is considered one of the primary target, as (i) its serum concentration is elevated in PAH patients (Humbert et al., 1995) and predicts survival (Soon et al., 2010); (ii) its overexpression induces pulmonary hypertension (PH) in mice (Steiner et al., 2009); and (iii) inhibition of its signaling pathway prevents and reverses PH in animal models by, at least in part, reducing the apoptosis-resistant threshold in PASMCs (Tamura et al., 2018). Although other evidence connect immune dysregulation to PAH, such as protection against PH development in xenograft lung cancer models in immunodeficeint mice (Pullamsetti et al., 2017) and the presence of circulating autoantibodies (Kuebler et al., 2018), the beneficial effect of anti-inflammatory treatments remains limited in some human PAH subtypes. 2.2. DNA damage response Fig. 2. Pathological factors contributing to vascular remodeling in PAH by stimulation of pulmonary artery smooth muscle cell (PASMC) expansion. ECM, extracellular matrix.
Efficient detection and repair of DNA damage is crucial for cell survival. In agreement with the two-step model for PAH development, it has been demonstrated that early PAEC dysfunction was associated with an enhanced susceptibility to DNA damage, a condition amplified by genetic loss of BMPR2 signaling or hypoxia (Diebold et al., 2015; Li et al., 2014). However, in the setting of disease progression, PAH cells exhibit sustained proliferation and survival, indicating that cells have 10
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family transcriptional known to dictate cell phenotypic conversion (Ranchoux et al., 2015). Using lineage tracing in genetically modified mice, Suzuki et al. (2018) provided further convincing evidence that EndMT occurs in PAH models. In addition, they demonstrated in the Sugen/hypoxia model of PAH that around 15% of PAECs lost their specific marker to gain expression of the smooth muscle cell marker αSMA (Suzuki et al., 2018). In light of these studies, EndMT appears to be an important contributor to vascular remodeling in PAH and suggests that modulation of its signaling may prove useful in treating the disease, although its relative contribution/clinical impact remains to be defined.
mounted protective responses to counteract the threats posed by DNA damage. Indeed, enhanced expression of Poly(ADP)-ribose-1 (PARP-1), a component of the DNA damage/repair machinery was observed in PAH-PASMCs (Meloche et al., 2014). Furthermore, overexpression of the transcription factor Forkhead box protein M1 (FOXM1) was shown to prevent DNA damage accumulation by stimulating the expression of the DNA damage sensor Nijmegen breakage syndrome 1 (Bourgeois et al., 2018). Consistently, pharmacological inhibition of PARP-1 and FOXM1 has clearly demonstrated therapeutic benefits in animal models mimicking PAH (Bourgeois et al., 2018; Meloche et al., 2014). Thus, targeting factors that keep non-deleterious levels of DNA damage to induce intolerable DNA damage levels has recently emerged as an exciting avenue of new treatments for PAH, currently tested in a clinical trial (NCT03251872).
2.5. Epigenetics Although a detailed description of epigenetic modifications in PAH is beyond the scope of the present review (for a comprehensive review, see (Pullamsetti et al., 2016)), histone modification, DNA methylation and non-coding RNA production play a key role in the pathogenesis of PAH affecting virtually all pathways responsible for the cancer-like phenotype of PAH cells (Boucherat et al., 2017). Among the epigenetic changes directly contributing to PAH development and progression, it has been reported that DNA methyltransferase (DNMTs)-dependent hypermethylation of the Superoxide dismutase 2 (SOD2) enhancer/ promoter regions (Archer et al., 2010) occurs in PAH patients as well as PAH rat model, leading to SOD2 gene repression, impairment of redox signaling and sustained proliferation of PASMCs. More recently, hypermethylation of the BMPR2 promoter was documented in patients with heritable PAH, which could influence the penetrance of mutation carriers (Liu et al., 2017). Apart from DNA methylation alterations, increased expression of nuclear-located Histone deacetylases (HDACs, responsible for the removal of the acetyl groups from histones, chromatin accessibility and gene silencing) and Bromodomain-containing 4 (BRD4, which binds to acetylated histones and transcription factors) was observed in lungs from PAH patients (Meloche et al., 2015b; Zhao et al., 2012). Pharmacological inhibition of HDACs or BRD4 was shown to improve PAH in different animal models (Meloche et al., 2015b; Zhao et al., 2012), highlighting the importance of epigenetic in the initiation and progression of PAH. However, concerns about cardiovascular side effects from broad-spectrum HDAC inhibitors were noted. Indeed, Bogaard et al. (2011) demonstrated that suppression of HDAC affects the adaptive response to the right ventricle (RV) to pressure overload precipitating RV failure (Bogaard et al., 2011). Multiple studies have also demonstrated a direct link between microRNA (miRNA) dysregulation and PAH development. Indeed, miR223 and miR-204 down-regulation in PAH-PASMCs was identified as a mechanism accounting for enhanced PARP-1 and FOXM1 expression, respectively, and thus protecting against accumulation of DNA damage (Bourgeois et al., 2018; Meloche et al., 2015a). Similarly, a reduced level of miR-34a was documented to favor PAH-PASMC proliferation and resistance to apoptosis in targeting multiple targets such as Plateletderived growth factor receptor alpha (Wang et al., 2016) and components of the mitochondrial fission machinery (Chen et al., 2018b). Conversely, up-regulation of miR-138 and miR-25 was reported in PAHPASMCs contributing to reducing the expression of the mitochondrial calcium uniporter (MCU) and consequently, inhibition of glucose oxidation, enhancement of mitochondrial fission and sustained cell proliferation (Hong et al., 2017). In a therapeutic perspective, nebulized anti-miR-138 restored MCU expression and regressed established PAH in the monocrotaline rat model (Hong et al., 2017). Moreover, recent studies have identified miR-140 as a hub regulating key PAH signaling pathways (Rothman et al., 2016). Finally, the implication of long noncoding RNAs (lncRNA) represents an exciting new field of research and some of them have been pinpointed as key regulators of PAH development by regulating PASMC proliferation (Chen et al., 2018a). Although PAH epigenetics is still in its infancy, studies have already helped identify a battery of druggable targets for therapeutic
2.3. Metabolism Metabolic dysfunction is a hallmark of PAH cells (Fig. 2). Like cancer cells, PAH cells undergo major metabolic transformations in a process called reprogramming, favoring glycolysis and fatty acid oxidation over oxidative phosphorylation (OXPHOS) (Ryan and Archer, 2015). During disease progression, this metabolic shift coordinated at the transcriptional level by the normoxic activation of the transcription factor Hypoxia-inducible factor 1-alpha (HIF-1α) directly contributes to the greater proliferative and survival capacity of PAH cells (Fig. 2). Indeed, HIF-1α was shown to stimulate the expression of pyruvate dehydrogenase kinase (PDK), which inactivates the pyruvate dehydrogenase (PDH) and thus decreases the metabolism of pyruvate into the mitochondria. Furthermore, inhibition of mitochondrial OXPHOS and activation of Dynamin-related protein-1 by HIF-1α was documented to perturb the mitochondrial fusion and fission balance in PAHPASMCs towards exaggerated fission. Although the mechanism remains to be clarified, mitochondrial fragmentation triggers PAH-PASMCs proliferation and resistance to apoptosis (Ryan and Archer, 2015). As a consequence of its critical role in PAH development and progression, metabolic-targeting therapies have been tested. Among them, administration of dichloroacetate (DCA), an inexpensive inhibitor of PDK successfully used to limit cancer progression in experimental models, demonstrated significant clinical effects in genetically susceptible PAH patients receiving background therapies (Michelakis et al., 2017). In addition to altered mitochondrial shape, differences in the mitochondrial protein profile have been also reported. For instance, similar to that observed in cancer cells, specific accumulation of the molecular chaperone Heat Shock Protein-90 (HSP90) was detected in hyperproliferating PAH-PASMCs (Boucherat et al., 2018). Further analyses revealed that this pool of HSP90 compartmentalized in mitochondria of diseased cells represents a protective mechanism against stress by stabilizing different proteins involved in the maintenance of mitochondrial DNA integrity and bioenergetics and thus ensuring cell survival. Importantly, treatment with a mitochondria-targeted HSP90 inhibitor called Gamitrinib (Kang et al., 2009), which does not affect cytosolic HSP90 function, specifically reduced the proliferative capacity of PAHPASMCs and improved established PAH in two animal models (Boucherat et al., 2018). 2.4. Endothelial-Mesenchymal transition Endothelial-mesenchymal transition (EndMT) is a biological process, known to favor PA thickening during normal development (Arciniegas et al., 2005), in which PAECs transdifferentiate into mesenchymal cells. Excessive EndMT is a newly recognized source of PASMCs/fibroblasts during PAH progression (Good et al., 2015; Ranchoux et al., 2015). Exposure of PAECs to inflammatory mediators (Good et al., 2015; Takagi et al., 2018) or loss of BMPR2 function (Ranchoux et al., 2015) were shown to converge and promote expression of key factors such as Twist-related protein 1, Snail and Snail 11
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interventions. Faced to the multifactorial nature of PAH, the “one drug/ multiple targets with a net favorable effect” strategy provided by epigenetic compounds may represent a promising approach.
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Medicine in focus
Pulmonary arterial hypertension: New pathophysiological insights and emerging therapeutic targets Alice Bourgeoisa, Junichi Omuraa, Karima Habbouta, Sebastien Bonneta, Olivier Boucherata,b, a b
T ⁎
Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC, Canada Department of Medicine, Université Laval, Québec, QC, Canada
A R T I C LE I N FO
A B S T R A C T
Keywords: Vascular remodeling Metabolism Epigenetic DNA damage
Pulmonary arterial hypertension (PAH) encompasses a group of clinical entities characterized by sustained vasoconstriction and progressive vascular remodeling that act in concert to elevate pulmonary vascular resistance. The current treatments for PAH are mainly dedicated to target the process of vasoconstriction and do not offer a cure. There is now accumulating evidence that expansion of pulmonary artery cells due to increased proliferation and apoptotic evasion is a key pathological component of vascular remodeling that occurs in PAH. Thus, vascular lesions seen in advanced PAH patients present some cancer-like characteristics offering important avenues for exploration and expanding treatment options. In this review article, we will discuss recent advances into mechanisms underlying disease progression, with a focus on pulmonary artery smooth muscle cells.
1. Introduction
PA vascular cells, including PA smooth muscle cells (PASMCs), adventitial fibroblasts, but also PAECs themselves (Figs. 1 and 2). These alterations lead to a gradual narrowing of the vascular luminal and possibly to complete occlusion. Currently approved drugs for PAH, mainly dedicated to reduce the pulmonary vasomotor tone, do not cure the disease and only confer modest mortality and quality of life benefits (Lajoie et al., 2016). In view of this, the pathogenic paradigm of PAH has gradually shifted away from vasoconstriction towards much greater focus on vascular remodeling with significant research effort directed toward deciphering the molecular mechanisms allowing PA cells (especially PASMCs) to survive and hyper-proliferate, notwithstanding exposure to chronic damaging stresses (Boucherat et al., 2017). Considering that the phenotype of PAH cells in an advanced stage of the disease is quite similar to that observed in cancer cells, this suggests that lessons learned from the field of oncology may provide valuable insights into PAH pathogenesis, and indirectly that drugs currently used in cancer and demonstrating safety profiles could be repurposed to tackle PAH. While inflammation and genetic abnormalities are key factors of PAH pathogenesis, determining the role of DNA damage response, metabolic reprogramming, endothelial-mesenchymal transition and epigenetics have become a major focus in PAH research and substantial effort are directed towards identifying clinical targets.
Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by vasoconstriction and vascular remodeling of distal pulmonary arteries (PAs), resulting in a persistent elevation of the mean PA pressure above 25 mmHg at rest, and ultimately in right heart failure (Lau et al., 2017). PAH is classified into subgroups based on etiology, including idiopathic, heritable (corresponding mostly with heterozygous germline Bone morphogenetic protein receptor-type 2, BMPR2 mutations), drug-induced (e.g. appetite suppressants, methamphetamine, etc.) and associated with other conditions (e.g. scleroderma, HIV, etc.) (Lau et al., 2017). Regardless of their etiology, all forms of PAH exhibit similar pulmonary vascular lesions suggesting shared pathological mechanisms. Mounting evidence supports the concept that development of PAH follows a biphasic pattern; a model supported by studies showing that apoptotic drugs able to reverse advanced PAH (Schermuly et al., 2005), at the expense of severe side effects (Hoeper et al., 2013), also predispose to development of the disease (Guignabert et al., 2016). Indeed, due to genetic predisposition and exposition to numerous insults (e.g. oxidative and shear stresses, inflammation), PA endothelial cell (PAEC) dysfunction is recognized as the primary event that causes PAH. In this model, PAECs that undergo apoptosis liberate a variety of cytokines and growth factors creating conditions that subsequently stimulate vessel constriction along with favoring the emergence of highly proliferative and apoptosis-resistant
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Corresponding author at: Pulmonary Hypertention Research Group, IUCPQ Research Centre, 2725, chemin Sainte-Foy, Québec, QC, G1V 4G5, Canada. E-mail address: [email protected] (O. Boucherat).
https://doi.org/10.1016/j.biocel.2018.08.015 Received 16 April 2018; Received in revised form 24 August 2018; Accepted 29 August 2018 Available online 03 September 2018 1357-2725/ © 2018 Elsevier Ltd. All rights reserved.
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Fig. 1. Schematic progression of pulmonary arterial hypertension. Following endothelial dysfunction, distal pulmonary arteries (PAs) undergo progressive vascular remodeling associated with exaggerated proliferation and resistance to apoptosis of PA resident cells. This structural change progressively results in occlusion of the pulmonary vascular lumen and contributes to elevations of pulmonary vascular resistances (PVR) and PA pressure. As a result of pressure-overload, the right ventricle (RV) initially compensates by an increase in hypertrophy and contractibility to maintain cardiac output (CO). In most of patients, however, these compensatory mechanisms fail and premature death occurs.
2. Pathogenesis 2.1. Immune dysregulation As a result of perivascular accumulation of immune cells (such as macrophages, lymphocytes, dendritic and mast cells), a myriad of proinflammatory mediators have been documented to be increased in PAH patients, collectively contributing to the initiation and progression of vascular remodeling (Kuebler et al., 2018). Among them, the interleukin-6 (IL-6) is considered one of the primary target, as (i) its serum concentration is elevated in PAH patients (Humbert et al., 1995) and predicts survival (Soon et al., 2010); (ii) its overexpression induces pulmonary hypertension (PH) in mice (Steiner et al., 2009); and (iii) inhibition of its signaling pathway prevents and reverses PH in animal models by, at least in part, reducing the apoptosis-resistant threshold in PASMCs (Tamura et al., 2018). Although other evidence connect immune dysregulation to PAH, such as protection against PH development in xenograft lung cancer models in immunodeficeint mice (Pullamsetti et al., 2017) and the presence of circulating autoantibodies (Kuebler et al., 2018), the beneficial effect of anti-inflammatory treatments remains limited in some human PAH subtypes. 2.2. DNA damage response Fig. 2. Pathological factors contributing to vascular remodeling in PAH by stimulation of pulmonary artery smooth muscle cell (PASMC) expansion. ECM, extracellular matrix.
Efficient detection and repair of DNA damage is crucial for cell survival. In agreement with the two-step model for PAH development, it has been demonstrated that early PAEC dysfunction was associated with an enhanced susceptibility to DNA damage, a condition amplified by genetic loss of BMPR2 signaling or hypoxia (Diebold et al., 2015; Li et al., 2014). However, in the setting of disease progression, PAH cells exhibit sustained proliferation and survival, indicating that cells have 10
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family transcriptional known to dictate cell phenotypic conversion (Ranchoux et al., 2015). Using lineage tracing in genetically modified mice, Suzuki et al. (2018) provided further convincing evidence that EndMT occurs in PAH models. In addition, they demonstrated in the Sugen/hypoxia model of PAH that around 15% of PAECs lost their specific marker to gain expression of the smooth muscle cell marker αSMA (Suzuki et al., 2018). In light of these studies, EndMT appears to be an important contributor to vascular remodeling in PAH and suggests that modulation of its signaling may prove useful in treating the disease, although its relative contribution/clinical impact remains to be defined.
mounted protective responses to counteract the threats posed by DNA damage. Indeed, enhanced expression of Poly(ADP)-ribose-1 (PARP-1), a component of the DNA damage/repair machinery was observed in PAH-PASMCs (Meloche et al., 2014). Furthermore, overexpression of the transcription factor Forkhead box protein M1 (FOXM1) was shown to prevent DNA damage accumulation by stimulating the expression of the DNA damage sensor Nijmegen breakage syndrome 1 (Bourgeois et al., 2018). Consistently, pharmacological inhibition of PARP-1 and FOXM1 has clearly demonstrated therapeutic benefits in animal models mimicking PAH (Bourgeois et al., 2018; Meloche et al., 2014). Thus, targeting factors that keep non-deleterious levels of DNA damage to induce intolerable DNA damage levels has recently emerged as an exciting avenue of new treatments for PAH, currently tested in a clinical trial (NCT03251872).
2.5. Epigenetics Although a detailed description of epigenetic modifications in PAH is beyond the scope of the present review (for a comprehensive review, see (Pullamsetti et al., 2016)), histone modification, DNA methylation and non-coding RNA production play a key role in the pathogenesis of PAH affecting virtually all pathways responsible for the cancer-like phenotype of PAH cells (Boucherat et al., 2017). Among the epigenetic changes directly contributing to PAH development and progression, it has been reported that DNA methyltransferase (DNMTs)-dependent hypermethylation of the Superoxide dismutase 2 (SOD2) enhancer/ promoter regions (Archer et al., 2010) occurs in PAH patients as well as PAH rat model, leading to SOD2 gene repression, impairment of redox signaling and sustained proliferation of PASMCs. More recently, hypermethylation of the BMPR2 promoter was documented in patients with heritable PAH, which could influence the penetrance of mutation carriers (Liu et al., 2017). Apart from DNA methylation alterations, increased expression of nuclear-located Histone deacetylases (HDACs, responsible for the removal of the acetyl groups from histones, chromatin accessibility and gene silencing) and Bromodomain-containing 4 (BRD4, which binds to acetylated histones and transcription factors) was observed in lungs from PAH patients (Meloche et al., 2015b; Zhao et al., 2012). Pharmacological inhibition of HDACs or BRD4 was shown to improve PAH in different animal models (Meloche et al., 2015b; Zhao et al., 2012), highlighting the importance of epigenetic in the initiation and progression of PAH. However, concerns about cardiovascular side effects from broad-spectrum HDAC inhibitors were noted. Indeed, Bogaard et al. (2011) demonstrated that suppression of HDAC affects the adaptive response to the right ventricle (RV) to pressure overload precipitating RV failure (Bogaard et al., 2011). Multiple studies have also demonstrated a direct link between microRNA (miRNA) dysregulation and PAH development. Indeed, miR223 and miR-204 down-regulation in PAH-PASMCs was identified as a mechanism accounting for enhanced PARP-1 and FOXM1 expression, respectively, and thus protecting against accumulation of DNA damage (Bourgeois et al., 2018; Meloche et al., 2015a). Similarly, a reduced level of miR-34a was documented to favor PAH-PASMC proliferation and resistance to apoptosis in targeting multiple targets such as Plateletderived growth factor receptor alpha (Wang et al., 2016) and components of the mitochondrial fission machinery (Chen et al., 2018b). Conversely, up-regulation of miR-138 and miR-25 was reported in PAHPASMCs contributing to reducing the expression of the mitochondrial calcium uniporter (MCU) and consequently, inhibition of glucose oxidation, enhancement of mitochondrial fission and sustained cell proliferation (Hong et al., 2017). In a therapeutic perspective, nebulized anti-miR-138 restored MCU expression and regressed established PAH in the monocrotaline rat model (Hong et al., 2017). Moreover, recent studies have identified miR-140 as a hub regulating key PAH signaling pathways (Rothman et al., 2016). Finally, the implication of long noncoding RNAs (lncRNA) represents an exciting new field of research and some of them have been pinpointed as key regulators of PAH development by regulating PASMC proliferation (Chen et al., 2018a). Although PAH epigenetics is still in its infancy, studies have already helped identify a battery of druggable targets for therapeutic
2.3. Metabolism Metabolic dysfunction is a hallmark of PAH cells (Fig. 2). Like cancer cells, PAH cells undergo major metabolic transformations in a process called reprogramming, favoring glycolysis and fatty acid oxidation over oxidative phosphorylation (OXPHOS) (Ryan and Archer, 2015). During disease progression, this metabolic shift coordinated at the transcriptional level by the normoxic activation of the transcription factor Hypoxia-inducible factor 1-alpha (HIF-1α) directly contributes to the greater proliferative and survival capacity of PAH cells (Fig. 2). Indeed, HIF-1α was shown to stimulate the expression of pyruvate dehydrogenase kinase (PDK), which inactivates the pyruvate dehydrogenase (PDH) and thus decreases the metabolism of pyruvate into the mitochondria. Furthermore, inhibition of mitochondrial OXPHOS and activation of Dynamin-related protein-1 by HIF-1α was documented to perturb the mitochondrial fusion and fission balance in PAHPASMCs towards exaggerated fission. Although the mechanism remains to be clarified, mitochondrial fragmentation triggers PAH-PASMCs proliferation and resistance to apoptosis (Ryan and Archer, 2015). As a consequence of its critical role in PAH development and progression, metabolic-targeting therapies have been tested. Among them, administration of dichloroacetate (DCA), an inexpensive inhibitor of PDK successfully used to limit cancer progression in experimental models, demonstrated significant clinical effects in genetically susceptible PAH patients receiving background therapies (Michelakis et al., 2017). In addition to altered mitochondrial shape, differences in the mitochondrial protein profile have been also reported. For instance, similar to that observed in cancer cells, specific accumulation of the molecular chaperone Heat Shock Protein-90 (HSP90) was detected in hyperproliferating PAH-PASMCs (Boucherat et al., 2018). Further analyses revealed that this pool of HSP90 compartmentalized in mitochondria of diseased cells represents a protective mechanism against stress by stabilizing different proteins involved in the maintenance of mitochondrial DNA integrity and bioenergetics and thus ensuring cell survival. Importantly, treatment with a mitochondria-targeted HSP90 inhibitor called Gamitrinib (Kang et al., 2009), which does not affect cytosolic HSP90 function, specifically reduced the proliferative capacity of PAHPASMCs and improved established PAH in two animal models (Boucherat et al., 2018). 2.4. Endothelial-Mesenchymal transition Endothelial-mesenchymal transition (EndMT) is a biological process, known to favor PA thickening during normal development (Arciniegas et al., 2005), in which PAECs transdifferentiate into mesenchymal cells. Excessive EndMT is a newly recognized source of PASMCs/fibroblasts during PAH progression (Good et al., 2015; Ranchoux et al., 2015). Exposure of PAECs to inflammatory mediators (Good et al., 2015; Takagi et al., 2018) or loss of BMPR2 function (Ranchoux et al., 2015) were shown to converge and promote expression of key factors such as Twist-related protein 1, Snail and Snail 11
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interventions. Faced to the multifactorial nature of PAH, the “one drug/ multiple targets with a net favorable effect” strategy provided by epigenetic compounds may represent a promising approach.
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