The article is from ~ China Pharmaceutical Biotechnology, No. 3, 2021
Author: Yang Guang, Wang Lei, Wu Shouzhen
Author Affilications:710021 Xi'an Medical College (Yang Guang); 710003 Xi'an Children's Hospital Cardiology Department (Wang Lei), Department of Clinical Laboratory (Wu Shouzhen)
Pulmonary arterial hypertension (PAH) is a malignant cardiopulmonary disease in which progressive increases in pulmonary artery pressure from a variety of etiologies, culminating in right-sided heart failure and even death. PAH has a variety of etiology, difficulty in early clinical diagnosis, and low long-term survival. It is believed that genetic and environmental factors are involved in the pulmonary vascular remodeling process of PAH, of which heredity is PAH, especially idiopathic pulmonary arterial hypertension (IPAH) and heritable pulmonary arterial hypertension (HPAH) is an important factor in the development of 25% to 30% Onset of patients with IPAH is associated with Mendelian genetic factors [1]. Since the bone morphogenetic protein type II receptor (BMPR2) was found to be a PAH susceptibility gene, researchers have discovered numerous PAH susceptibility genes.
1 TGF-β signaling pathway-related genes
1.1 BMPR2
The BMPR2 gene, located on chromosome 2q31-32[2], encodes the TGF-β superfamily member BPR2 protein, and approximately 370 PAH-associated BMPR2 mutation genotypes have been identified, of which unsense mutations, missense mutations, code shift mutations, and gene rearrangements are the most common [3]. 70% to 80% of HPAH and 10% to 20% of IPAH are associated with BMPR2 variation. In patients with PAH, BMPR2 mutants have an average onset of 10 years earlier, an increase in pulmonary vascular resistance of approximately 35%, an increase in mean pulmonary artery pressure of 8 mmHg, a decrease in cardiac output of approximately 15%, a lower responsiveness to acute vasodilation tests (3 versus 16 percent), and a higher risk of death and lung transplantation in younger age groups (mean age 35.4 years) [4]. In the classical signaling pathway, when binding to BMP ligands, BMPR (ActRIIA and ActRIIB) recruits, compounds, and phosphoriesize BMP-1 receptors, further phosphorylating downstream SMADs, which form complexes with general-purpose SMADs such as SMAD4, and transfer to the nucleus to bind to the DNA sequence of the BMP response element; therefore, the complex acts as a transcriptional regulator by binding to BMP that plays a key role in cell proliferation, apoptosis, and migration Reaction elements, including DNA binding inhibitors 1, 2, and 3 (ID1, ID2, ID3) or cyclin-dependent kinase inhibitors 1A and 2B (CDKN1A and CDKN2B), regulate target gene expression. In addition to the classic SMADs signaling pathway, BMPR2 activates several atypical BMP signaling pathways, including p38 mitogen-activated protein kinase (MAPK), extracellular signal-modulating kinase (ERK), phosphoinositol 3-kinase (PI3K)/Akt signaling, peroxisome proliferation activator γ (PPARγ)/apolipoprotein E (ApoE)/HDLC), Wnt pathway, cellular protein, Rho-GTPases, protein kinase C (PKC) signaling, and the Notch signaling pathway[5], BMPR2 regulate cell proliferation, differentiation, and apoptosis through a variety of these mechanisms.
A large number of studies have confirmed that dysfunctional BMPR2 signaling is a key feature of PAH. The expression of the BMPR2-BRCA1 axis in patients with IPAH to maintain the stability of the pulmonary vascular endothelial cell environment, DNA damage repair and gene stability was significantly downregulated, resulting in abnormal DNA repair and apoptosis resistance, causing severe damage to endothelial cells, vascular remodeling and hemodynamic changes[6]; inflammatory cytokines IL-1β, TNF-α downregulated BMPR2 expression, inducing endothelial cells to transform into stromal cells, these cell pairs BMP9 induces more sensitive osteogenesis differentiation, which ultimately leads to wall calcification[7]; HIV viral proteins induce proliferation of lung smooth muscle cells by negatively regulating BMPR2 expression through miR-126a[8]; BMPR2 mutants to abnormal mitochondrial function and insulin metabolism in cardiomyocytes, increased insulin resistance in cardiomyocytes, decreased glucose uptake, and enhanced lipid uptake, resulting in changes in lipid toxicity in the right ventricle of PAH[9]; in one case, HPAH Genetic analysis of children with hereditary hemorrhagic telangiectasia (HHT) revealed a new mutation in BMPR2[10], supporting the conclusion that bronchial vessels, pulmonary arteriovenous veins, and capillary networks are more likely to form abnormal anastomosis in BMPR2 mutants [11]. All abnormal signals are ultimately attributed to the common pathway of endothelial and smooth muscle cell dysfunction, accompanied by imbalances in apoptosis and proliferative signals, vasoconstriction, and structural changes in the vascular wall, progressive occlusion of distal pulmonary vessels leading to pulmonary vascular resistance and increased right ventricular afterload, leading to right ventricular failure and death [5]. In recent years, there are three main ideas for targeted therapy of BMPR2: (1) targeting and regulating BMPR2 receptors to increase their activity; (2) increasing receptor availability on the cell surface by modulating the signal upstream of BMPR2; and (3) reconstructing the downstream signal of BMPR2 through the signaling pathway of targeted interactions. Recombinant BMP9 prevents endothelial cell apoptosis and improves clinical symptoms of PAH [12]. Some drugs have shown good pharmacological effects, such as tacrolimus activating downstream classical and non-classical BMPR2 signaling pathways through the dual inhibition of FKBP12 and calcineurin, which has been suggested by clinical Phase IIa trials as a good safety and tolerability [13]. Targeted injection of the BMPR2 gene into PAH mice using adenovirus vectors found improvements in their muscularized blood vessels, and although no human trials have been conducted, there is still good prospect for genetic intervention [14]. The PKC pathway signaling inhibitor enzatoline is effective in reversing the PAH-associated phenotype [15], and chaperone 4-phenylbutyric acid (4-PBA) increases receptor utilization by increasing the frequency with which BMPR2 travels to the cell membrane surface [16]. Etanercept and paclitaxel can increase BMPR2 signal transduction by negatively modulating the TGF-β inhibitory pathway [17]. In vitro trials have shown that FK506 and Nzatolin show additive effects on BMPR2 signal activation, and further exploration of the potential additive effects of BMPR2 receptors and their downstream signals may have therapeutic value [15].
BMPR2 has an epigenetic rate of approximately 20 percent [18], suggesting that other factors are involved in its epigenetic process. Women with harmful BMPR2 mutants are more likely to develop PAH than men [19]. There is growing evidence that the synthesis of PAH and endogenous estrogens is associated with metabolic dysfunction and accumulation of mitosis estrogen metabolites. 16-Hydroxyestrone (16OHE1) inhibits normal BMP pathway signaling and increases the penetrance of BMPR2 mutations. Interestingly, the methoxy metabolite of estrogen instead has a protective effect on pulmonary vascularity [20]. Obesity can also be involved in the onset of PAH by influencing estrogen metabolism [21], and aromatase is an important enzyme for endogenous estrogen synthesis, and small clinical trials have shown that its inhibitor Anastrozole improves 6-minute walking trials in men and menopausal women [22]. The latest study has identified a new cardioprotective E2-ERα-BMPR2-apelin axis that also provides a new direction for targeted therapy for the right ventricle of PAH [23]. Animal experiments have found that with the increase of age, the cardiac output, pulmonary vascular resistance, and systemic circulatory pressure of experimental mice all show an aggravating trend, and the pAH penetrance rate increases [24]. In addition, microribonucleic acid (miRNA) often regulates gene expression by inhibiting related translational processes, especially miR-29, miR-124, miR-140, and miR-204 as PAH biomarkers and therapeutic targets, and the efficacy of some drugs based on artificial supplementation of miRNA analogues or inhibition of specific miRNA expression is still in clinical trials [26]. Clinical assays of miRNAs and their molecules themselves are unstable, transport patterns, and non-target effects remain a major challenge in this area [27-28]. PAH patients with obvious metabolic disorders, pulmonary vascular endothelial cell aerobic metabolism decreased, glycolysis increased, glutamine decomposition increased, fatty acid oxidation decreased, accelerated carbon monoxide metabolism and other changes caused by abnormal proliferation of endothelial cells, vascular proliferation and right heart remodeling phenotype, abnormally high expression of arginase through the cleavage of arginine, reduce endothelial dependence of nitric oxide synthase (eNOs), so that vasodilation function is impaired, in addition, reducing and oxidizing the cell environment, tricarboxylic acid cycle and other metabolic pathways are also abnormal, These studies have provided many new targets for PAH therapy, and there are already some drugs targeting the glucose metabolic pathway, such as the pyruvate dehydrogenase kinase inhibitor dichloroacetate and glycolytic enzyme enolase (ENO) targeting PFKFB3, which has achieved some success in reducing glucose metabolism and improving right ventricular function in PAH model rats [29]. These studies suggest that multiple factors, including sex and age, are involved in the onset of PAH. In the context of harmful BMPR2 mutations, there may also be a variety of genetic factors and environmental "secondary blows" that also contribute to the onset of PAH, which needs to be further explored [30].
1.2 ALK1
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by telangiectasia of the mucocutaneous mucosa, recurrent nosebleeds, and arteriovenous malformations(especially in the lungs, liver, and cranial vascular malformations), HHT often combined with PAH [31]. Important genetic causes of HHT are mutations in genes encoding activin receptor-like kinase 1 (ALK1) and endolin (ENG) receptors. Chen et al. [32] studies showed ALK1 and ENG variability of 57.1% and 14.3%, respectively, in Han Chinese populations, and two new mutation sites were found in exons 8 and 14 of ENG. The occurrence of PAH is closely related to BMP pathway inhibition and abnormal activation of the TGF-β pathway, and improving ALK1/ENG protein expression and improving its function is the key to breakthrough treatment. A variety of regulators have been identified in cell and animal experiments, including: (1) PI3K inhibitors, which inhibit arteriovenous malformation formation; (2) tyrosine kinase inhibitor TKIS, which improves anemia and gastrointestinal bleeding; (3) integrin activator CXCL12, which binds endothelin to the corresponding integrins on white blood cells, pericytes, or platelets; (4) BMP9 acts upstream of ENG and ALK1, whose blockade can aggravate HHT symptoms; and (5) oxysterol and other nuclear LXR agonists can upregulate ENG expression ;(6) Soluble endothelin, TRC105, and ACE-041, all of which have anti-angiogenic effects, are important for further study of these targets and are critical for the diagnosis and treatment of PAH [33].
2 Non-TGF-β signaling pathway-related genes
2.1 KCNK3
KCNK3 encodes TASK-1 (K2P3.1), a two-pore potassium channel present in a variety of cell membranes, including human PASMCs, and its primary role is to maintain the resting potential of the cell membrane and regulate pulmonary vascular tone [34]. Ma et al. [35] By studying a primary PAH lineage, six KCNK3 missense mutations, including c.608G→A (G203D), confirmed that the gene was a candidate gene for PAH pathogenicity, and these heterozygous missense mutations were harmful mutations, electrophysiological studies showed that they could all lead to loss of ion channel function, and the phosphatase inhibitor ONO-RS-082 improved some of the function of the damaged channel. Studies have shown that 1.3% of IPAH and 3.2% of HPAH carry these mutant genes, and two-quarters of KCNK3 mutation carriers have no clinical manifestations, suggesting that KCNK3 mutations are incompletely explicit. In 2016, Navas Tejedor et al. [36] discovered two new missense mutations in the gene (p. Gly106Arg and p.Leu214Arg), p.Gly106Arg, are the first KCNK3 homozygous mutations found that may be highly conserved by modifying glycine located at position 106 of the potassium channel transmembrane protein, which is normally between the intramembrane and transmembrane regions. In 2017, researchers discovered Japan's first KNCK3 mutation (p. Gly203Asp）[37]。 It was found that KCNK3 knockout, the mouse pulmonary vascular smooth muscle cell membrane resting K+ current is significantly weakened, showing a depolarizing excitatory state, the lung tissue extensive microvascular contraction, the right ventricular systolic blood pressure increased, the terminal pulmonary blood vessels (diameter < 30 μm) density increased, microvascular muscleization, collagen extensive cross-linking. Vascular endothelial cytoprotective factor CD31 and VWF are expressed out of balance, resulting in vascular endothelial damage [38]. The expression of HIF1-α in MICE PASMCs was upregulated, and the susceptibility to hypoxia in pulmonary vessels increased; the Thr308 phosphorylation signaling pathway of ERK1/2 and Akt was activated; and the expression of vivotin in members of the apoptosis inhibition gene family increased; all of these pathways could lead to abnormal proliferation of PASMCs, forming the pathological basis of PAH. Electron microscopy observed the endothelial cell membrane of PAH model mice with missing KCNK3 expression, and the distribution of nest proteins on the surface was abnormal, and the structure of the fossa became shallow, suggesting that KCNK3 may regulate endothelial cell function by affecting endothelial cell material transport and signal transduction; similar to the BMPR2 mutation, the human siRNA-KCNK3-hPASMCs cell model found that the mitochondrial membrane was similar to the cell membrane depolarization, and part of the mitochondrial membrane was cleaved, which further confirmed PAH Onset is associated with subcellular structural and functional abnormalities. The latest study [39] found that vitamin D deficiency PAH cardiomyocyte surface voltage gating and acid-sensitive potassium ion current weakened, endothelial cell function deteriorated, PASMCs depolarization, arterial muscleization, causing moderate increase in pulmonary artery pressure, may be related to VDR target gene expression imbalance, vitamin D active form of calcitriol can significantly increase KCNK3 expression, improve clinical symptoms, given the large number of VDR target genes, and early prevention value, further in-depth study of VDR should be studied Related genes and their molecular mechanisms.
2.2 TopBP1
TopBP1 is homologous to the C-terminal BRCT domain of human breast cancer 1 protein (BRCA1) and is critical in protein ligation, DNA replication initiation, transcriptional regulation, DNA damage repair, and cell cycle "checkpoints" [40]. In 2013, de Jesus Perez et al. [41] confirmed TopBP1 as a susceptible gene for IPAH through total extrogen sequencing. The expression of TopBP1 in vascular endothelial cells in IPAH patients decreased, which increased the susceptibility to ENDOthelial CELL DNA damage and apoptosis, and repairing its expression could significantly reduce apoptosis and improve vascular damage; further functional studies found that p.S817L was a mutation of unclear significance, p.R309C was a pathogenic mutation, and p.N1042S was a benign mutation, suggesting that a simple gene mutation could not be the only causative factor of PAH, and there were other factors affecting its clinical characterization. Further functional studies are needed to elucidate potential factors affecting protein function in mutant genes [42]. BRCA1 regulates BMPR2 expression through the BMPR2-BRCA1 loop[6], suggesting that TopBP1, which contains homologous structures, may also affect BMPR2 expression through similar or other mechanisms.
2.3 TBX4
Mutations in TBX4 (T-Box transcription factor 4) (possibly other nearby loci, including TBX2) are currently considered to be a syndrome characterized by abnormal variable expression, such as skeletal dysplasia (including hand and foot development abnormalities), developmental delay, hearing loss, congenital heart defects (e.g., patent ductus arteriosus, atrial septal defects, aortic valve defects), and PAH [43]. Studies have found that TBX4 mutation rates are higher in children than in adults, the French TBX4-related PAH study shows female dominance, the age distribution is bimodal, usually in childhood or after the age of 40 years [44], and like BMPR2-associated PAH, female dominance indicates that sex factors are involved in the PAH pathogenesis of TBX4 mutants, and it is worth noting that TBX4 mutations often have pulmonary development defects [45], which also brings new changes to the PAH classification, exactly tbX4 mutations of PAH Whether patients are abnormal or genetic factors in lung development, further exploration of the molecular and other characteristics of TBX4 signaling is needed, particularly with the study of pulmonary vascular system and phenotypic variation.
2.4 CBLN2
CBLN2 is currently the only PAH susceptibility gene confirmed by genome-wide association studies, which increases the risk of PAH by 1.97 times [46], and has been studied [47-48] in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and systemic lupus erythematosus pulmonary hypertension (SLE-PAH), and at present, CBLN2 as a PAH susceptibility gene, the specific mechanism has yet to be elucidated.
2.5 Newly discovered pathogenic genes
Gräf et al. [49] Discovered new PAH pathogenic genes (ATP13A3, AQP1, SOX17, GDF2) by whole genome sequencing of 1038 patients in the experimental group and non-PAH subjects in the control group. In the experimental group, the age of diagnosis of PAH for AQP1 and SOX17 mutations was significantly earlier than the age of diagnosis (51.7 + 16.6) years in PAH patients without genetic mutations [(32.8 width=2.4, height=0.6± width=2.4, height=0.616.2) years, Pwidth=2.4, height=0.6= width=2.4, height=0.60.002 years and (36.9 width=2.4, height=0.6±width=2.4, height=0.6 14.3) years, Pwidth=2.4, height=0.6=width=2.4, height=0.6 0.013]. Functional studies have shown that ATP13A3 mRNA is expressed in PASMCs, while the deletion of ATP13A3 inhibits endothelial cell proliferation and increases apoptosis, which is consistent with pathological changes in PAH. Gelinas et al. [50] first reported ATP13A3 mutations in children, and little is known about the function of ATP13A3 in vascular cells and its molecular mechanisms, and further research is needed. GDF2 mutations result in decreased BMP9 and BMP10 cycle levels, which inform strategies for treating PAH by enhancing the BMP9 or BMP10 signal in PAH [51]. AQP1 encodes aquaporins on cell membranes involved in endothelial cell migration and vascular regeneration[52], and animal experiments have found that absence of AQP1 expression of PASMCs improves the clinical characteristics of PAH rat models induced by hypoxia[53], suggesting that further research is needed to clarify the effect of AQP1 mutations on water molecule transport function and the specific cell types and related mechanisms that affect them during the pathogenesis of PAH. Aldosterone promotes the onset of pulmonary hypertension by stimulating the expression of aquaporins and proliferation of pulmonary smooth muscle cells, and spironolactone inhibits the proliferation of smooth muscle cells by modulating AQP1 and β-catenin. A study of patients with HPAH and IPAH in Japan confirmed that SOX17 is a PAH susceptibility gene [55]. Another study of 256 patients with PAH [56] found that SOX17 mutations developed in 0.7% of PATIENTS with IPAH and 3.2% of patients with congenital heart disease associated with PAH (PAH-CHD), and that most of the missense mutations in SOX17 occurred in the highly conserved HMG domain, where significant enrichment of the mutation could be found in the developing heart and vascular tissue, suggesting that the mutation was a risk factor for congenital heart disease and IPAH, for further study of SOX17, for The high incidence of PAH-CHD in children is of great significance. SOX17 is involved in the pathogenesis of PAH by interacting with multiple PAH signaling pathways and transcriptional targets, and repairing SOX17 expression and signal transduction may be a new strategy for the treatment of PAH [57].
3 Genetic counseling
Mutant genes have been found in ipah, HPAH, PAH-CHD and pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis (PVOD/PCH), and France provides genetic counseling and genetic testing for the above-mentioned high-risk populations, 2015 The European Society of Cardiology (ESC) and the European Respiratory Society (ERS) published guidelines for the diagnosis and treatment of pulmonary hypertension recommend genetic counseling and testing for adults and children with PAH or PVOD/PCH disease, as well as adult relatives at risk of carrying susceptible mutations. Clinicians should inform these high-risk groups and their family members of genetic risks, as technically permitted, for screening and early diagnosis. Genetic testing in the family should begin with the affected individual, and if the family mutation is known and an unaffected family member tests negative for the mutation, then that member has the same risk of PAH as the general population, which not only helps to assist in the diagnosis, but also provides adequate psychological comfort; even if genetic testing is not performed, the patient should be informed of its clinical signs and symptoms to ensure that the diagnosis is time-sensitive. In view of the incomplete penetrance, reproductive problems, genetic discrimination, and various psychosocial problems that accompany genetic diseases, adequate genetic education and counseling should be carried out before genetic testing, which requires professional clinicians, genetic counselors, geneticists, and testing institutions to complete [1].
4 Outlook
Since the 1950s, genetic research on PAH has developed rapidly, not only revealing the reasons for the development of PAH from the genetic and molecular levels, driving the clinical diagnosis and treatment of PAH, but also opening the way for targeted drug therapy and greatly improving its clinical prognosis. However, the field still faces a number of problems that need to be solved urgently: (1) the research is difficult: PAH is related to multiple causes and systems, often combined with other diseases, and the gold standard for diagnosis (right heart catheter manometry) is strict, resulting in its research is often limited by the selection criteria, and the efficacy of single-center research is not good, it is best to carry out multi-center research; (2) the mechanism is not clear: many susceptible genes found so far only show correlation, but their specific signaling pathways and molecular mechanisms are not fully understood, and new potential susceptibility genes have yet to be discovered ;(3) Insufficient epigenetic research: neonatal mutations, loci heterogeneity, and incomplete effusion of multiple mutated genes, including BMPR2, suggest that PAH genotype and phenotype are not one-to-one correspondence, and how gene modification and environmental factors play a role in the development of PAH still needs to be explored in depth. PAH genetic research is a huge challenge, but its prospects are broad, and further deepening research in this field is of great significance for understanding the development of PAH, developing new targeted drugs, improving clinical diagnosis and treatment, and guiding fertility.
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Fund Project: Major Research Project of Xi'an Science and Technology Program (2017123SF/YX017(2)), Xi'an Bureau-level Scientific Research Project (J201601002)
Received:2021-02-20
DOI: 10.3969/j.issn.1673-713X.2021.03.013