Abstract: Pulmonary arterial hypertension (PAH) is a rare group of disorders with poor prognosis, characterized by progressively increased pulmonary arterial pressure and resistance. The pathological changes include pulmonary vasoconstriction and remodeling, abnormal proliferation of pulmonary smooth muscle and endothelial cells, and thrombosis, etc. The pathogenesis of PAH is complex. pathways, and other abnormalities. This provides additional theoretical basis for the treatment and prevention of pulmonary hypertension.
Keywords: pulmonary hypertension; bone forming protein type II receptor; activin receptor-like kinase; peroxisome proliferator-activated receptor γ; Rho kinase
CICS： R725 文献标志码： A 文章编号： 1000-3606（2009）05-0406-04
Advance in the basic research on pulmonary arterial hypertension GU Hong (Department of Pediatric
Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China)
Abstract: Pulmonary arterial hypertension (PAH) is defined as a group of diseases characterized by a rapidly
The pathology of PAH includes vasoconstriction, vascular wall remodeling, hyperplasia of the pulmonary arterial pressure and pulmonary vascular resistance. The pathology of PAH includes vasoconstriction, vascular wall remodeling, hyperplasia of pulmonary artery smooth muscle cells and pulmonary endothelial cells, in situ thrombosis. The etiology of PAH is complex, multifactorial, and likely involves the genetic predisposition such as mutations in bone morphogenetic protein receptor-II and activin receptor- like kinase 1. In addition, the down-regulation of peroxisome proliferator-activated receptors activity, over-expression of RhoA/Rho kinase may play a critical role in pathophysiology. This finding will provide more theoretical basis on prevention and treatment of this disease. Pediatr, 2009, 27(5):406-409)
Key words：pulmonary arterial hypertension; bone morphogenetic protein receptor-II; actin receptor-like kinase 1; peroxisome proliferator- activated receptor γ; Rho kinase
Pulmonary arterial hypertension (PAH) is a rare group of disorders with a poor prognosis characterized by increased pulmonary artery pressure and resistance. Pulmonary hypertension is defined as a mean pulmonary artery pressure > 25 mmHg in the quiet state and > 30 mmHg during exercise. The pathogenesis of pulmonary hypertension is complex, and factors involved in its development include pulmonary vasoconstriction and remodeling, abnormal proliferation of pulmonary vascular smooth muscle and endothelial cells, thrombosis and genetic abnormalities. Some recent advances in research on the pathogenesis and etiology of pulmonary hypertension are presented.
1. Genes related to pulmonary hypertension
1.1 Bone formation protein type II receptor gene
Nichols et al [1, 2] conducted a genetic analysis of familial PAH families in 1997 and found an abnormality in the short arm of chromosome 2, part 2q31-q32, suggesting that the causative gene for pulmonary hypertension (PPH1 gene) may be present in this region. This new finding has advanced the molecular etiology of PAH. Subsequently, Deng et al [3, 4] in 2000 further identified the PPH1 gene as a bone morphogenetic protein (BMP) type II receptor (BMPR2) gene belonging to the transforming growth factor-beta superfamily.
In Europe and the United States, abnormalities of the BMPR2 gene are present in 50% of familial PAH and 26% of idiopathic PAH [5, 6]. In a study of 79 cases in Japan, BMPR2 gene abnormalities were found in 100% of familial PAH and 30% of idiopathic PAH [7]. In addition, the BMPR2 gene variant was not found in PAH cases with combined collagen vascular disease [8], but was found in some cases of PAH with congenital heart disease and PAH due to diet pills [9, 10]. This suggests that the BMPR2 gene may be involved in the pathogenesis of the remaining types of pulmonary hypertension, in addition to familial and idiopathic PAH.
1.2 Activin receptor-like kinase genes
1.2.1 Hereditary hemorrhagic telangiectasia (HHT) HHT is a hereditary disease with abnormal development and structure of the blood vessel wall, the incidence is about 1/8000. (3) arteriovenous malformations (brain, lung, liver, spinal cord, digestive tract, etc.); (4) family history. The causative genes of HHT are thought to be the activin receptor-like kinase 1 (ALK1) and endoglin (ENG) genes belonging to the TGF-β superfamily [11] [12], of which ALK1 consists of 503 amino acids. amino acids, which is similar to the amino acid composition of BMPR2.
1.2.2 The ALK1 gene abnormality in pulmonary hypertension was found to be caused by mutations in the ALK1 gene in HHT with PAH in 2001 [13]. In 2005, Harrison et al [16] identified ALK1 gene mutations in a patient with idiopathic PAH without HHT at 18 months of age. In 2008, Fujiwara et al [17] analyzed pediatric familial PAH and idiopathic PAH without HHT and found five cases with ALK1 mutations. Each of these cases was identical to the PAH cases with HHT onset, with mutations in the kinase activity domain. Since patients with HHT usually develop at an older age, it is possible that some of the PAH patients with pediatric onset may develop HHT in the future.
1.3 Gene mutations and the pathogenesis of pulmonary hypertension
The TGF-β superfamily signaling system has a variety of biological functions, including regulation of cellular function and tissue cell differentiation. In this signaling system, type II receptors (BMPR2, etc.) on the cell surface bind to type I receptors (ALK1, etc.) and form a tetramer. The tetramer is phosphorylated upon binding to the corresponding ligand, and further causes phosphorylation of intracellular Smad proteins. The phosphorylated Smad protein enters the nucleus with the common pathway Smad and acts as a transcriptional regulator to inhibit cell proliferation. Therefore, it is hypothesized that in PAH patients, abnormalities in the BMPR2 or ALK1 gene, which is one of the cell surface receptors, lead to blockage of downstream signaling pathways, resulting in proliferation control of cells associated with the pulmonary vascular wall and consequently pulmonary hypertension.
2, Proliferation of pulmonary vascular endothelial cells and peroxisome proliferator-activated receptors
The peroxisome proliferator-activated receptor (PPAR) is a member of the ligand-dependent cytosolic hormone receptor superfamily, which is widely present in various tissues in vivo and plays an important role in the regulation of adipocyte and monocyte differentiation and maturation as well as tumor cell proliferation and differentiation. PPAR includes three isoforms: α, β and γ. Among them, PPARγ is abundantly expressed in adipose tissues and is associated with atherosclerosis and insulin resistance while regulating adipose metabolism and cell differentiation.
Recent studies have revealed that PPARγ is expressed in immune cells, vascular endothelium, vascular smooth muscle, digestive tract and lung tissues, and exerts various roles [18, 19]. For example, it induces apoptosis, including tumor cells [20-22], inhibits vascular regeneration [21], regulates vascular smooth muscle cell proliferation, and terminates or inhibits the cell cycle.
Ameshima et al [23], in comparing patients with severe PAH with normal lung tissue and lung tissue from chronic obstructive pulmonary disease (COPD), found that the expression of PPARγ was significantly reduced in PAH patients both at the gene level and at the protein level. In immunostaining of lung tissue with anti-PPARγ monoclonal antibodies in severe PAH, PPARγ expression was found to be significantly reduced in plexiform lesions of the pulmonary vasculature. In addition, factor VIII-positive and smooth muscle actin-negative cell populations with significantly lower caspase 3 activity were observed in the plexiform lesions. These findings suggest that the abnormal proliferation of cells in small arterial occlusive lesions in severe PAH lacks apoptotic mechanisms despite their endothelial properties, suggesting that this abnormal endothelial cell function may be associated with low levels of PPARγ expression with apoptosis-inducing functions.
3.Rho kinase signaling pathway
The Rho family of small guanosine triphosphate (GTP)-binding proteins is a member of the Ras superfamily with a relative molecular weight of (20-30)×103. The main members of the Rho family are RhoA, RhoB, and RhoC, the most important of which is RhoA. The Rho kinase signaling pathway plays an important role in various cellular physiological functions such as cell contraction, proliferation, migration and gene expression [25-27]. high expression or overactivation of Rho kinase is closely associated with the development of many cardiovascular diseases including pulmonary hypertension, and Rho kinase is emerging as a new target for the treatment of pulmonary hypertension.
3.1 Basic Research on Rho Kinase Inhibitors
Rho kinase inhibitor fasudil has been used for the prevention and treatment of PAH in a rat model of monocrotaline (MCT)-induced PAH (MCT model) [28]. The administration of MCT-induced PAH to the rats was started at the same time as the administration of fasudil, and a significant improvement in survival was found. Subsequently, rats with MCT that had developed pulmonary hypertension were administered with fasudil, which also resulted in improved survival. In the MCT model, Rho kinase activity was enhanced, endothelial cell function was reduced, and vascular smooth muscle was hypercontracted in the pulmonary arteries of the rats. The histological findings of this study also showed that fasudil inhibited the hypertrophy of the middle pulmonary artery and myelination of the small pulmonary arteries in MCT rats. In addition, transoral administration of fasudil also had a therapeutic effect in mice with hypoxia-induced pulmonary hypertension [29]. Inhalation of fasudil via the airway
has also been shown to lower pulmonary artery pressure in rats with other causes of pulmonary hypertension [30].
3.2 Clinical studies of Rho kinase inhibitors in the treatment of pulmonary hypertension
In a clinical study of pulmonary hypertension treated with Rho kinase inhibitors, Fukumoto et al [31] found that intravenous fasudil was effective in reducing pulmonary vascular resistance in patients with severe PAH who were not effectively treated with inhaled oxygen, nitric oxide, and oral calcium channel blockers. Rho kinase may be involved in the pathophysiological mechanisms of PAH formation, such as endothelial cell dysfunction, pathological changes in the pulmonary vascular wall and persistent pulmonary artery constriction. The role of Rho kinase in the development of PAH is still unknown. If the long-term therapeutic effect of Rho kinase inhibitors on PAH can be demonstrated in future clinical trials, then Rho kinase inhibitors will become a new treatment option for PAH.
In conclusion, PAH is a group of pathophysiological syndromes with complex pathogenesis and a poor clinical prognosis, eventually progressing to right heart failure and death. The more prominent advances in the pathophysiology and molecular biology of pulmonary hypertension in recent years have facilitated the development of drug therapy and brought new hope to patients with pulmonary hypertension.
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