Although the research on pulmonary hypertension machine made significant progress in the 1990s, which caused a revolution in targeted therapy for pulmonary hypertension, some patients with pulmonary hypertension have poor results after treatment or even healing is still poor, so we need to further improve the current therapeutic strategies and find new aetiological treatment pathways based on endothelial cell damage and loss of function and smooth lung cell proliferation in the occurrence and development of pulmonary hypertension Based on the role of endothelial cell damage and apoptosis and smooth lung cell proliferation in the development of pulmonary hypertension, future therapeutic targets for pulmonary hypertension should be related to the function of endothelial cells and smooth muscle cells. Ni Xinhai, Department of Cardiovascular Medicine, Fu Wai Hospital, Beijing, China
1. 5-Hydroxytryptamine receptor and transporter function
5-hydroxytryptamine has the function of promoting vasoconstriction and promoting cell mitosis, which is considered as one of the possible causative factors of pulmonary hypertension [41]. -hydroxytryptamine transporters also appear to be upregulated [42], and drugs that downregulate 5-hydroxytryptamine transporters, such as 5-hydroxytryptamine reuptake inhibitors, may have a therapeutic effect on pulmonary hypertension.
2.Vasoactive intestinal polypeptide
Vasoactive intestinal polypeptide (VIP) is secreted by a variety of cells and has an anti-proliferative effect, it is also a neuropeptide with vasodilatory effect, vasoactive intestinal polypeptide is insufficient in patients with idiopathic pulmonary arterial hypertension (IPAH), Brown JH et al. reported 8 cases of patients with IPAH after applying vaso Brown JH et al. reported that eight patients with IPAH showed significant improvement in clinical symptoms and hemodynamic indices after applying vasoactive intestinal polypeptide 200ug/d by inhalation [43]. Vasoactive intestinal polypeptide may be used in the treatment of patients with IPAH.
3. Rho kinase inhibitors
Rho, the Ras homolog, was obtained in 1985 in the study of Ras-related genes in rainbows, and the Rho family of GTPases is a member of the Ras monomeric GTPase superfamily. Rho regulates a variety of biological behaviors and functions of cells, including contraction, adhesion, migration, proliferation, apoptosis, and gene expression, by activating downstream Rho kinases [44.45.46.47]. Rho kinases belong to the family of serine/threonine protein kinases that receive Rho-transduced activation signals, undergo activation by phosphorylation of multiple amino acid sites, and mediate a series of downstream phosphorylation/dephosphorylation reactions.Key signaling molecules of the Rho/Rho kinase signaling pathway include Rho GTPase, Rho kinase, and myosin light chain phosphatase (MLCP), and the downstream target molecules include myosin light chain phosphatase, myosin, ERM family proteins, endocannabinoids, and LIM kinase, etc. MLCP was the first substrate identified for Rho kinase and is the predominant substrate. binding subunit (MBS) by activated Rho kinase, which inactivates MLCP, and the inactivated MLCP is unable to dephosphorylate the actin light chain (MLC), which has increased levels of MLC phosphorylation and increased actin-myosin cross-linking, leading to contraction and polymerization of the actin microfilament backbone [48.49].
Rho kinase mediates hypoxia-induced reduction in endothelial-type nitric oxide synthase (eNOS) expression, resulting in decreased NO production, and the Rho kinase inhibitors fasudil or Y-27632 reduce Rho kinase activity and inhibit vasoconstriction [50]. Inhalation of fasudil in patients with pulmonary hypertension significantly reduces pulmonary vascular resistance, but pulmonary arterial pressure is not significantly reduced [51], and intravenous fasudil not only significantly reduces pulmonary vascular resistance, but also significantly reduces pulmonary arterial pressure and increases cardiac index, with a small reduction in arterial pressure in the body circulation. dependent vasodilation, inhibit proliferation and promote apoptosis of pulmonary artery smooth muscle cells [52]. Therefore, the Rho/Rho kinase signaling pathway may be involved in the formation of pulmonary hypertension due to multiple causes, and Rho/Rho kinase inhibitors may be able to treat pulmonary hypertension.
4. Growth factor inhibitors
Uncontrollable vascular remodeling is a characteristic manifestation of pulmonary arterial hypertension, and monoclonal-like proliferation is seen in the plexiform lesions of IPAH, where the cells grow at a rate and in a manner similar to that of malignant tumors, and recent studies have shown that platelet-derived growth factors play an important role in the development and progression of pulmonary vascular remodeling in pulmonary arterial hypertension [53], and in 2005 Ghofrani HA et al. first in the New England Journal reported a case of familial pulmonary hypertension in which the combination of anti-pulmonary hypertensive drugs was ineffective and a trial of the tyrosine kinase inhibitor imatinib (an anti-cellular proliferative agent) 200 mg daily for 3 months resulted in a significant reduction in pulmonary vascular resistance and significant improvement in cardiac index and exercise tolerance without significant side effects [54]. Subsequently, animal experiments and case reports of imatinib for pulmonary hypertension have continued [55.56.57], and anti-cellular proliferative agents may be a new way to treat severe pulmonary hypertension.
5. Inhibitors of HMG-CoA reductase
Inhibitors of β-hydroxy-β-methylglutaryl CoA (HMG-CoA) reductase have effects on vascular physiology, anti-inflammatory and proliferative vascular lesions that are not regulated by lipid-lowering effects, Kao PN et al. 2005 reported the efficacy of the oral HMG- CoA reductase inhibitor simvastatin in treating patients with clinical pulmonary hypertension, a total of l2 cases of primary pulmonary hypertension and A total of 12 patients with primary pulmonary hypertension and 4 patients with secondary pulmonary hypertension were given simvastatin in addition to conventional therapy and were followed up for 1-3 years. Simvastatin has been preliminarily shown to be effective in the treatment of pulmonary hypertension and may have good prospects for application [58].Laudi S et al. found that right ventricular pressure, right ventricular wall hypertrophy and vascular remodeling were significantly reduced in rats with wild lily of the valley-induced pulmonary hypertension treated with 10 mg/d atorvastatin for 28 days compared to controls, and 5-hydroxytryptamine expression was reduced.The therapeutic effect of atorvastatin and 5 serotonin expression was correlated with reduced 5-hydroxytryptamine expression [59].Li M et al. found that simvastatin reduced vasotocin-induced matrix metalloproteinase and endothelin-1 release via inhibition of the Rho/Rho kinase pathway in pulmonary vascular smooth muscle cells, suggesting that simvastatin attenuated pulmonary vascular remodeling [60].Satoh K et al. found that pravastatin was able to reduce vascular remodeling by inhibiting stromal cell-derived factor-1/ chemokine CXC receptor 4 (SDF-1/CXCR4) and cell adhesion molecule-1/CD18 (ICAM-1/CD18) pathways to reduce bone marrow-derived progenitor cell migration and implantation thereby improving hypoxia-induced pulmonary hypertension [61].Barreto AC et al. 60 patients with pulmonary hypertension were randomized into rosuvastatin statin 10 mg/d treatment group and placebo treatment group and found that plasma P-selectin was significantly lower in the treatment group compared to the control group at 1, 3 and 6 months, P-selectin plays an important role in inflammation and thrombosis, thus rosuvastatin can act on the pathophysiological process of pulmonary hypertension by reducing P-selectin [62].
6. cytological treatment
Endothelial cell damage plays an important role in the occurrence and development of pulmonary hypertension, and Zhao YD et al. found that injection of endothelial progenitor cells into an animal model of pulmonary hypertension reduced pulmonary vascular damage, especially when these cells were transfected with nitric oxide synthase, which converts arginine precursors into nitric oxide [63].
V. Summary In the formation of pulmonary hypertension, the following three pathways play an important role: 1. Arachidonic acid pathway: leads to a decrease in PGI2 and an increase in TXA2, causing vascular smooth muscle cell contraction; 2. NO pathway: decreased NO synthesis, decreased cGMP levels, and smooth muscle cell contraction; 3. Endothelin pathway: causes smooth muscle cell contraction. New drugs such as prostacyclin analogs, type 5 phosphodiesterase inhibitors and endothelin receptor antagonists have been developed for these pathways respectively, and have been used in clinical practice successively. The quality of life and prognosis of patients with pulmonary hypertension have improved significantly, but there are still some patients whose symptoms worsen after receiving monotherapy or who have difficulty tolerating treatment due to drug side effects. Combination drug therapy works through different mechanisms to reduce the dose of drugs administered and mitigate the adverse reactions and side effects caused by excessive doses, and although drug combination therapy is effective, it is costly. New drugs for the treatment of pulmonary hypertension are still under further research, including 5-hydroxytryptamine reuptake inhibitors, vasoactive intestinal polypeptides, Rho kinase inhibitors, growth factor inhibitors, HMG- CoA reductase inhibitors, cellular and gene therapy and immunomodulators.