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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 64
| Issue : 3 | Page : 115-124 |
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Pulmonary arterial hypertension and flavonoids: A role in treatment
Jialing Wang1, Hailong Li2, Tian Xia1, Jun Feng1, Ru Zhou3
1 Department of Pharmacology, College of Pharmacy, Ningxia Medical University, Yinchuan, China
2 The Third People's Hospital of Ningxia, Yinchuan, China
3 Department of Pharmacology, College of Pharmacy; Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education; Ningxia Characteristic Traditional Chinese Medicine Modernization Engineering Technology Research Center, Ningxia Medical University, Yinchuan, China
| Date of Submission | 07-Apr-2021 |
| Date of Decision | 26-May-2021 |
| Date of Acceptance | 27-May-2021 |
| Date of Web Publication | 19-Jun-2021 |
Correspondence Address:
Prof. Ru Zhou
Department of Pharmacology, College of Pharmacy, Ningxia Medical University, 1160 Shengli street, Yinchuan 750004
China
 Source of Support: None, Conflict of Interest: None  | 4 |
DOI: 10.4103/cjp.cjp_25_21
Pulmonary arterial hypertension (PAH) is a high mortality progressive pulmonary vascular disease that can lead to right heart failure. The use of clinical drugs for the treatment of PAH is limited to a great extent because of its single target and high price. Flavonoids are widely distributed in nature, and have been found in fruits, vegetables, and traditional Chinese medicine. They have diverse biological activities and various pharmacological effects such as antitumor, antioxidation, and anti-inflammatory. This review summarizes the progress in pharmacodynamics and mechanism of flavonoids in the treatment of PAH in recent years, in order to provide some theoretical references for relevant researchers.
Keywords: Flavonoids, pulmonary arterial hypertension, treatment
How to cite this article:
Wang J, Li H, Xia T, Feng J, Zhou R. Pulmonary arterial hypertension and flavonoids: A role in treatment. Chin J Physiol 2021;64:115-24 |
Jialing Wang and Hailong Li contributed equally to this work.
| Introduction | |  |
Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease characterized by pulmonary vascular remodeling and increased pulmonary artery pressure, which can lead to right heart failure with high mortality. Epidemiological data showed that the prevalence of PAH is 1% in the general population, and the prevalence rate can reach 10% in people over 65.[1],[2],[3] The 6th PAH conference put the mean pulmonary artery pressure (mPAP) >20 mmHg above the normal value on the line. According to the hemodynamic characteristics, pathophysiological mechanisms, and clinical manifestations, PAH can be divided into five categories: arterial PAH, left heart disease-related PAH, pulmonary disease/hypoxia-related PAH, PAH caused by pulmonary obstruction, and PAH caused by unknown or multiple factors.[4] The occurrence of PAH is closely related to a variety of factors, involving abnormalities in a variety of signaling pathways inside and outside the cell, but regardless of the type of PAH, excessive pulmonary vasoconstriction, pulmonary vascular remodeling, and in situ thrombosis are common pathologies that lead to PAH basis.
Although great progress has been made in the understanding and pathogenesis of PAH, the prognosis of the disease is still extremely poor, with a median survival time of less than 3 years.[5] Many studies on clinical patients and related animal models of PAH have shown that a variety of complex mechanisms are involved in the occurrence of PAH. At present, the treatment of PAH is focused on targeted drug therapy and surgical treatment; although these treatments can improve the hemodynamics and quality of life of patients, the treatment cost and the singleness of action target limit its use to a great extent.[6] A national study in China shows that more than 50% of PAH patients do not use any PAH-specific therapy because of their financial burden.[7] Exploring the pathogenesis of PAH and developing safe, effective, targeted, and low-cost drugs is a hot topic in medical and pharmaceutical research.
A large number of studies have confirmed that flavonoids have shown good application potential in the prevention and treatment of cardiovascular diseases due to their anti-inflammatory, anti-oxidant, anti-proliferation, and other pharmacological activities.[8],[9],[10] Based on the results of in vivo and in vitro studies on PAH, we summarized the effects and mechanisms of flavonoids in the treatment of PAH, aiming to provide a basis for deepening the understanding of PAH and provide a theoretical basis for clinical research.
Flavonoids
Flavonoids are not uncommon in nature and are a series of compounds derived from 2-phenylchromone as the core [Figure 1]. Based on the C6-C3-C6 structure, flavonoids can be divided into flavones, flavonols, dihydroflavonoids, isoflavones, chalcones, etc., according to their different conformations. By consulting the literature, this review summarizes the flavonoids for the treatment of PAH. Their specific structures and mechanisms are shown in [Table 1] and [Table 2]. | Table 1: Types of flavonoids for treatment of pulmonary arterial hypertension
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 | Table 2: The mechanisms of flavonoids in the treatment of pulmonary arterial hypertension
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Flavonoids and cardiovascular disease clinical research
Flavonoids have been shown to have beneficial effects on cardiovascular diseases including regulating vascular function, blood pressure, and blood lipids.[16],[40],[43],[44] In human studies, apple can improve vascular endothelial function, lowers blood pressure, and reduces arterial stiffness; this effect is related to the high concentration of flavonoids in the apple skin.[45] Clinical studies have shown that consumption of purified anthocyanins can significantly increase high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, triglycerides, regulate blood pressure, and have benefits for cardiovascular diseases.[21],[46] Interestingly, eating berries such as strawberries and blueberries can also have the same effect, because berries are one of the important sources of anthocyanins.[47]
Protective effects of flavonoids on pulmonary arterial hypertension
Flavonoids and hemodynamic parameters
Human PAH is characterized by abnormal hemodynamic changes in pulmonary arteries including an obvious increase in mPAP and right ventricular systolic pressure (RVSP).[17] These parameters are also used as indicators to judge whether the PAH model is successful or not. In many PAH animal model studies, baicalin, grape seed proanthocyanidin extract (GSPE), and other flavonoids have been found to significantly improve the hemodynamic abnormalities of PAH animals.[23],[48]
Flavonoids and pulmonary vessels
The gradual thickening of pulmonary vascular wall contributes to the development of PAH.[15],[49] In previous researches, the ratio of pulmonary arterial wall area (WA%), ratio of pulmonary arterial wall thickness (WT%), and the expression of α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) were used to assess pulmonary artery remodeling in pulmonary arteries.[11] By means of histopathology and immunohistochemistry, it was found that WA% and WT% in PAH rats increased significantly, and the expression of PCNA and α-SMA in lung tissue increased, which was reversed after treatment with flavonoids such as isorhamnetin, which indicated that flavonoids could protect PAH by inhibiting pulmonary vascular remodeling.[50] The abnormal deposition of extracellular matrix plays an important role in the occurrence and development of PAH. When a large amount of collagen in the extracellular matrix is deposited, it will inevitably lead to hardening of the blood vessels, thickening of the vessel wall, contraction of the lumen, and decreased vascular compliance, which will cause hemodynamic changes and PAH.[51] Baicalin has been found to inhibit the synthesis and expression of collagen I in the pulmonary artery, which is helpful in the treatment of PAH.[52] Excessive pulmonary vasoconstriction can lead to increased pulmonary artery pressure, which is another pathological feature of PAH. Quercetin exerts an effective vasodilation effect on the pulmonary artery, which can be used to treat PAH.[33]
Flavonoids and right ventricle
PAH is a complex clinical syndrome. It starts from the pulmonary circulation and leads to a gradual increase in pulmonary vascular resistance and pulmonary vascular remodeling. Pulmonary vascular remodeling leads to a decrease in blood vessel diameter, which in turn leads to an increase in pulmonary artery pressure. In response, the heart gains stronger muscle contractility by increasing the size of cardiomyocytes and expanding the right ventricular wall. However, this initial compensatory activity eventually turns into right ventricular failure, which is the main determinant of PAH functional status and prognosis.[53],[54] In PAH animal models, it was observed that cardiomyocytes showed obvious proliferation and hypertrophy, accompanied by the upregulation of RVSP, right ventricular hypertrophy index, right ventricular mass index, and treatment with flavonoids such as chrysin and naringenin could improve these pathological changes and reduces right ventricular hypertrophy.[29],[55]
Pathophysiological mechanism of flavonoids in the treatment of pulmonary arterial hypertension
Flavonoids and oxidative stress
Oxidative stress plays an important role in the occurrence and development of PAH.[27],[39] Oxidative stress refers to the process that, when the body is stimulated by hypoxia, viruses, or other external stimuli, the reactive oxygen species (ROS) produced in cells or tissues have exceeded the endogenous antioxidant defense, resulting in the accumulation of oxidative damage in the body or cells. Endothelial cells are the main structural cells of pulmonary vascular intima, which have the functions of maintaining blood circulation, regulating vasomotor and blood coagulation. They can secrete endothelium-derived vasodilation factor nitric oxide (NO) and vasoconstrictor factor endothelin (ET), antagonist and regulate vascular relaxation.[26] The production of ROS can reduce the synthesis of endothelial NO synthase (eNOS), inhibits the production of NO, promotes the synthesis and release of ET and promotes vasoconstriction.[32] Studies have shown that ROS can change gene expression, phosphorylation of modified proteins to cause cascade reaction, induce platelets and macrophages to produce platelet-derived growth factor (PDGF), thus promoting the proliferation of pulmonary artery smooth muscle cells (PASMCs).[56] In addition, superoxide, hydrogen peroxide and ONOO- can activate matrix metalloproteinases (MMP), among which MMP-2 is one of the important causes of hypoxic and monocrotaline (MCT)-induced pulmonary vascular remodeling.[57]
Natural flavonoids have strong antioxidation, and the hydroxyl substituents on their basic skeleton are active groups for scavenging free radicals, which can avoid oxidative damage by inhibiting and scavenging free radicals and ROS.[58] Chrysin is a flavonoid in propolis. Studies have shown that 100 μM chrysin can significantly inhibit the upregulation of nicotinamide adenine dinucleotide phosphate 4 (NOX4) expression in PASMCs induced by hypoxia, reduced the production of ROS, and the increase of malondialdehyde (MDA) content.[29] Puerarin is one of the main isoflavones found in Pueraria lobata. Puerarin treatment can reduce the oxidative stress of human pulmonary artery endothelial cells (PAECs) induced by hypoxia in a dose-dependent manner and further protects human PAECs from hypoxia injury.[59] Similarly, Hawthorn leaf extract has been found to have endothelial protective effect, which is related to antioxidant mechanism.[41] Baicalein, a flavonoid extracted from Scutellaria baicalensis root, has been widely used in the treatment of cardiovascular disease. It has been found that baicalein 200 mg/kg treatment in rats with PAH for 2 weeks could significantly reduce the level of MDA in lung tissue, increased the activities of superoxide dismutase (SOD) and glutathione peroxidase, and improved pulmonary vascular remodeling by regulating oxidative stress.[42] Rutin has a significant scavenging effect on oxygen-free radicals in vivo and in vitro. Rutin can scavenge the production of ROS in PAECs and mitochondria, reduces the upregulation of NOX4 in PAECs and PASMCs induced by hypoxia, and participates in the pathogenesis of PAH. However, the mechanism of cellular signal pathway related to the antioxidant mechanism of rutin on hypoxia-induced pulmonary artery cell proliferation needs to be further explored.[20] The antioxidant effect of grape seed has been recognized all over the world, which is related to GSPE. GSPE has strong antioxidant activity and has a beneficial effect on cardiovascular system. It is reported that GSPE can increase the level of SOD and reduces the level of MDA in rats with hypoxia-induced PAH. GSPE inhibits the level of NOX4 gene and the production of ROS, thus alleviating oxidative stress damage.[48] In addition, isoglycyrrhizin, total flavonoids of vanilla, naringin, and hydroxysafflor yellow A (HSYA) have been proved to be beneficial to the regulation of oxidative stress markers in the model of PAH.[55],[60]
Flavonoids and inflammation
Inflammatory cells have been found in the peripheral blood vessels of many PAH animal models and patients with severe PAH. The vascular wall is composed of endothelial cells, smooth muscle cells, and fibroblasts. The contraction and relaxation of blood vessels maintain a balance in the physiological state. During immune inflammatory reaction, various inflammatory factors and oxygen-free radicals damage the endothelium, resulting in injury and dysfunction. The balance between vasodilating substances such as NO and ET-1 is broken, and the contractile ability of pulmonary vessels is increased abnormally. The secretion of growth factors and chemokines by inflammatory cells can promote the migration and abnormal proliferation of smooth muscle cells. There are also immune cells adhering to the adventitia fibroblast layer, which makes it muscular, and the pulmonary vascular structure is remodeled at this time, which aggravates PAH.[12],[34],[61],[62]
Flavonoids have significant anti-inflammatory effects, and their mechanism is mainly through the inhibition of the production and release of inflammatory factors and the interaction between cells. Luan et al. studied the therapeutic effect and mechanism of baicalin on MCT-induced PAH in rats. The results showed that baicalin downregulated nuclear factor kappa-B (NF-κB) signal pathway by inhibiting inflammation, thus protecting lung and heart from MCT injury, reducing pulmonary artery pressure, and reducing right ventricular hypertrophy.[23] Similarly, another flavonoid in Scutellaria baicalensis Georgi, baicalein (50 mg/kg) can also significantly reduce pulmonary vascular remodeling and improve PAH by inhibiting the activation of NF-κB.[42] Grape seed procyanidins (GSP) have significant anti-inflammatory and vascular protective effects. It has been found that GSP can not only reduce inflammation through PPAR-g/cyclooxygenase-2 pathway but also downregulates heat shock protein 70, affect the expression of pho-IκBα, and reverses the possible mechanism of pulmonary vascular remodeling.[35],[63] Carthamus tinctorius extract for injection is widely used in the treatment of cardiovascular and cerebrovascular diseases. HSYA is the main chemical component of C. tinctorius. It has been found that it plays a protective role in PAH by reducing the expression of inflammatory factors interleukin (IL)-1 β, IL-6, and tumor necrosis factor-α (TNF-α) in lung tissue of rats.[60] Li et al. found that dihydromyricetin (100 mg/kg) could effectively improve the expression of IL-6, TNF-α, and IL-10 in lung tissue of rats with MCT-induced PAH.[24] In addition, after the rats were given 50 mg/kg naringin for 3 weeks, it was found that the content of TNF-α in lung tissue decreased, indicating that naringin protected PAH by regulating inflammation.[55]
Flavonoids and proliferation
The proliferation of PASMCs plays an important role in the pathogenesis of PAH. Abnormal proliferation of PASMCs directly leads to the increase of vascular WT, stenosis of vascular lumen, obstruction of blood flow, and increase of pulmonary artery pressure. Therefore, how to reverse pulmonary artery remodeling has been the main target of PAH treatment.[18],[19]
The abnormal increase of intracellular Ca2+ concentration ([Ca2+]i) is a key factor in the proliferation of PASMCs. Bone morphogenetic protein 4 increases SOCE and [Ca2+]i by upregulating transient receptor potential channel-1 (TRPC1) and TRPC6, which promotes PASMCs proliferation and ultimately stimulates in pulmonary vascular remodeling.Dong et al. observed that chrysin could downregulate the expression of hypoxia-induced bone morphogenetic protein 4, TRPC in PASMCs, and exert its protective activity against PAH by regulating [Ca2+]i.[31] Wei et al. found that, in the PASMCs proliferation model induced by PDGF-BB, hesperetin could regulate cyclin expression in a dose- and time-dependent manner, inhibit DNA synthesis, and regulate AKT/GSK3 β signaling pathway, improve the proliferation of PASMCs, which proved that it had the therapeutic potential to treat pulmonary vascular remodeling diseases.[22] High mobility group protein B1 (HMGB1) is a highly conserved nuclear protein widely distributed in mammalian cells. Under normal circumstances, HMGB1 is localized in the nucleus and released to the extracellular environment under inflammatory stimulation. It participates in tissues remodeling and angiogenesis activities promote the migration and proliferation of smooth muscle cells.[36],[64] As an inhibitor of HMGB1, glycyrrhizin can inhibit the proliferation of PASMCs and reduce the pulmonary vascular remodeling induced by MCT in PAH rats.[65] In in vitro experiments, Morales-Cano et al. found that quercetin could inhibit the proliferation of pulmonary artery smooth muscle.[33] Interestingly, He et al. also found that quercetin could significantly block G1/G0 cells, regulate cyclins, changed the proportion of Bax/Bcl-2, and inhibited TrkA/AKT signaling pathway, which was a potential candidate for the treatment of hypoxia-induced PAH.[66] Zhang et al. found that baicalin could reverse the hypoxia-induced decrease of p27 and the increase of AKT/protein kinase B phosphorylation of p-AKT in vivo and in vitro, effectively inhibiting the proliferation of PASMCs and improving hypoxic PAH.[67] In addition, baicalin reduces the abnormal proliferation of human PASMCs is also related to the inhibition of hypoxia-inducible factor-1α and AhR pathways.[68] Formononetin (FMN) is a kind of natural isoflavone with many cardioprotective properties. In the lung tissue of rats treated with FMN, it was observed that the expression of α-SMA and PCNA decreased, the expression of Bax/Bcl-2 and cleaved caspase-3 increased, and the phosphorylation of AKT and ERK decreased, thus providing protection against PAH induced by MCT.[69] In MCT-induced Wistar rat PAH model, isoquercetin significantly reduced the expression of PCNA and α-SMA. In PDGF-BB-induced PASMC proliferation model, isoquercetin could lead to cell cycle arrest in G0/G1 phase, downregulate the expression of cyclin D1 and cyclin-dependent kinase 4, and inhibit the degradation of p27Kip1. It negatively regulated the phosphorylation of PDGF-β, Akt/GSK3 β, and ERK1/2 induced by PDGF-BB, which proved that it could improve the pulmonary vascular remodeling induced by MCT by inhibiting the proliferation of PASMCs and blocking PDGF-Rβ signal pathway.[30] The occurrence of PAH is closely related to the bone morphogenetic protein pathway, and the mutation of bone morphogenetic protein receptor 2 (BMPR2) can lead to the proliferation of PASMCs. Through in vivo and in vitro experiments, Chang et al. found that isorhamnetin improved the expression of BMPR2, p-Smad1/5, and the gene expression of Id1 and Id3 in human PASMCs, the mechanism of inhibiting proliferation of PASMCs was related to the regulation of bone morphogenetic protein signal pathway.[50] Pretreatment with phytoestrogens genistein has also been shown to reduce the development of PAH by inhibiting the proliferation of PASMCs.[70]
Flavonoids and autophagy
Autophagy is a highly conservative lysosome degradation pathway in eukaryotic cells, which is mainly used to degrade long-lived proteins, damaged organelles, and intracellular invasive pathogenic microorganisms. There is a basic level of autophagy in the normal body, which is conducive to cell metabolism and the recycling of organelles; in some specific pathological environments, such as the production of a large number of cytokines, inflammatory factors, and oxidative stress, lead to abnormal autophagy, such as autophagy inhibition or excessive autophagy, so as to break the balance of the body and lead to the occurrence and development of the disease.[71] Many studies have found the role of autophagy in cell balance including cell survival, death and cardiovascular disease, and confirmed that autophagy can promote cell cycle progression, regulate the expression of cell cycle factors, and participate in pulmonary angiogenesis.[25],[28],[72],[73],[74] Zhang et al. used mRFP-GFP-LC3 fluorescence microscope and Western blotting found that puerarin could improve hypoxia-induced PAH and reduced the expression of autophagy markers in vivo and in vitro. In addition, puerarin improves hypoxia-induced PASMCs proliferation in an autophagy-dependent manner.[38]
Flavonoids and endothelial-to-mesenchymal transition
More and more studies have shown that endothelial interstitial transformation (endothelial-to-mesenchymal transition, EndMT) is involved in the occurrence and development of PAH, which is also an important pathological process of pulmonary vascular remodeling.[37] EndMT is a special form of epithelial–mesenchymal transition (epithelial–mesenchymal transition, EMT). In this process, the morphology and physiological function of endothelial cells change the endothelial phenotypes such as CD31 and VE-cadherin lose, the ability of tight gap junction between cells decreases, and then migrate to the inner layer of blood vessels and transform into smooth muscle-like mesenchymal cells. With the accumulation of a large number of these cells, the thickness of pulmonary vascular wall increases and promotes the occurrence of pulmonary vascular remodeling.[13] In MCT-induced PAH rat model, Shi et al. observed the upregulated expression of endothelial-interstitial transformation molecules N-cadherin, vimentin, Snail, and Slug, which proved the occurrence of endothelial-interstitial transformation, and it was reversed by baicalein (50 mg/kg and 100 mg/kg). Therefore, baicalein is considered to be a promising choice for the treatment of PAH.[75] Huang et al. used transforming growth factor-β1 to induce transdifferentiation of PAECs. Factor VIII immunofluorescence staining and α-SMA protein expression were used to determine the identification and transdifferentiation of PAECs. The results showed that quercetin effectively inhibited the transdifferentiation of PAECs and the activation of Akt/Erk1/2 cascade in cells, which had a protective effect on PAH.[76]
Flavonoids and vasoconstriction
PAH is the result of the imbalance between endothelium-derived vasoconstrictor and vasodilator. Pulmonary vasoconstriction plays a major role in the early development of various types of PAH.[77] When vascular endothelial cells are injured, pulmonary vascular endothelial function is abnormal, releasing a large number of vasoconstrictive substances such as ET-1; while vasodilating substances such as NO are reduced which lead to the imbalance of vasoconstrictor and vasodilator factors, and promote pulmonary vasoconstriction.[14],[78] Jiang et al. found that Trifolium pratense isoflavone diet in broilers with experimental PAH could reduce the level of ET-1 in the lungs, regulated the secretion of NO and ET-1, and promoted the expression of inducible NO synthase (iNOS), thus regulating pulmonary vasoconstriction.[79] Genistein could induce NO and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent vasodilation and reversed abnormal vasoconstriction in rats with hypoxic PAH in vitro.[80] A series of studies have shown that flavonoids naringin and chrysin could maintain the beneficial effects of NO, stimulated the expression of eNOS and inhibited harmful iNOS overexpression, and play a protective role in PAH by dilating pulmonary arteries.[55],[81]
Flavonoids and mitochondrial dependent apoptosis
Recent studies have shown that mitochondria play an important role in the occurrence and development of pulmonary artery remodeling.[82] Mitochondria is the main sites of ATP production, which participate in the processes of cell growth and differentiation, information transmission, and apoptosis. Small changes in mitochondria will affect the energy metabolism of cells and lead to the imbalance between proliferation and apoptosis.[83] Bcl-2 family is the key apoptosis regulator in the process of apoptosis. Mitochondria can regulate the Bcl-2 family, increase the expression of pro-apoptotic factor Bax, promote the penetration of mitochondrial cytochrome C into the cytoplasm, and start apoptosis.[84] It has been found that natural dietary flavonoid apigenin overinhibits hypoxia inducible factor-1α-KV1.5 channel to induce mitochondrial apoptosis in PASMCs, improve pulmonary vascular remodeling, and treat PAH.[85]
To sum up, flavonoids can alleviate the dysfunction of PAECs, the proliferation of PASMCs, and the synthesis of collagen outside of pulmonary artery fibroblasts through multiple pathways, thereby exerting the therapeutic effect of PAH [Figure 2]. | Figure 2: The mechanism of flavonoids in the treatment of pulmonary arterial hypertension. Flavonoids play a role in the treatment of pulmonary arterial hypertension through antioxidation, anti-inflammatory, anti-proliferation, anti-autophagy, antiendothelial–mesenchymal transition, anti-vasoconstriction, and antimitochondrial-dependent apoptosis.
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| Conclusion and Future Opportunities | | |
PAH is an extremely malignant disease with poor prognosis and difficult to cure. If early detection, early diagnosis, and early treatment can be achieved, the prognosis and long-term survival rate will increase accordingly. As far as the current research is concerned, there are still big differences in the compliance and affordability of some patients with clinical treatment drugs, and the pathogenesis of PAH needs to be further revealed. At present, there are three common types of targeted drugs for the treatment of PAH in clinical practice: prostacyclin analogs, type 5 phosphodiesterase inhibitors, and ET receptor antagonists, whose main role is to effectively relax blood vessels with a single mechanism of action. Although these drugs can improve patients' symptoms and delay the progression of the disease, they also have various deficiencies and serious side effects. Compared with targeted drugs in clinical applications, traditional Chinese medicines have complex active ingredients, which can treat PAH through multiple mechanisms and multiple targets, with small side effects and low prices, making their development promising. However, the identification, separation, and evaluation of active ingredients of traditional Chinese medicines are underdeveloped. A considerable part of traditional Chinese medicines are unclear. The dosage form and route of administration of traditional Chinese medicines are still very controversial, which severely limits the clinical application of traditional Chinese medicines. If the above problems can be solved, the treatment of PAH with traditional Chinese medicine will produce unexpected results.
Natural flavonoids have been widely proven to protect PAH by expanding the pulmonary artery, inhibiting the proliferation of PASMCs, and antioxidation. However, these studies are limited to animal models and lack clinical verification. Therefore, flavonoids are more in depth. The clinical research is imperative. In addition, the solubility and stability of flavonoids are generally poor due to their own molecular structure, and their biological absorption is limited. The structural modification of flavonoids and changing their solubility to improve bioavailability and biological activity are also research hot topics. It is believed that, in the near future, high efficiency and low-toxic flavonoids can be applied to specific clinical treatments to maximize the life of patients and improve the quality of life, and PAH will no longer be a catastrophic disease.
Financial support and sponsorship
This project was supported by Ningxia Hui Autonomous Region Key Research and Development Project (Grant No. 2019BFG02027); 2017 Ningxia Hui Autonomous Region Science and Technology innovation leader training project (Grant No. KJT2017005); 2017 Ningxia Medical University Youth Backbone Talent Cultivation Selected Project; Ningxia Hui Autonomous Region Key Research and Development Project (Grant No. 2020BEG03040); Ningxia Hui Autonomous Region Key Research and Development Project ForeignScience and Technology Cooperation Special (Grant No. 2018BFH03019).
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Kopeć G, Kurzyna M, Mroczek E, Chrzanowski Ł, Mularek-Kubzdela T, Skoczylas I, et al. Characterization of patients with pulmonary arterial hypertension: Data from the polish registry of pulmonary hypertension (BNP-PL). J Clin Med 2020;9:173.  |
| 2. | Cool CD, Kuebler WM, Bogaard HJ, Spiekerkoetter E, Nicolls MR, Voelkel NF. The hallmarks of severe pulmonary arterial hypertension: The cancer hypothesis-ten years later. Am J Physiol Lung Cell Mol Physiol 2020;318:L1115-30. |
| 3. | Ventetuolo CE, Aliotta JM, Braza J, Chichger H, Dooner M, McGuirl D, et al. Culture of pulmonary artery endothelial cells from pulmonary artery catheter balloon tips: Considerations for use in pulmonary vascular disease. Eur Respir J 2020;55:1901313. |
| 4. | Sahay S. Evaluation and classification of pulmonary arterial hypertension. J Thorac Dis 2019;11:S1789-99. |
| 5. | Swift AJ, Lu H, Uthoff J, Garg P, Cogliano M, Taylor J, et al. A machine learning cardiac magnetic resonance approach to extract disease features and automate pulmonary arterial hypertension diagnosis. Eur Heart J Cardiovasc Imaging 2021;22:236-45. |
| 6. | Nakamura K, Akagi S, Ejiri K, Yoshida M, Miyoshi T, Toh N, et al. Current treatment strategies and nanoparticle-mediated drug delivery systems for pulmonary arterial hypertension. Int J Mol Sci 2019;20:5885. |
| 7. | Chen Y, Lu W, Yang K, Duan X, Li M, Chen X, et al. Tetramethylpyrazine: A promising drug for the treatment of pulmonary hypertension. Br J Pharmacol 2020;177:2743-64. |
| 8. | Jimenez R, Lopez-Sepulveda R, Romero M, Toral M, Cogolludo A, Perez-Vizcaino F, et al. Quercetin and its metabolites inhibit the membrane NADPH oxidase activity in vascular smooth muscle cells from normotensive and spontaneously hypertensive rats. Food Funct 2015;6:409-14. |
| 9. | Srisook K, Srisook E, Nachaiyo W, Chan-In M, Thongbai J, Wongyoo K, et al. Bioassay-guided isolation and mechanistic action of anti-inflammatory agents from Clerodendrum inerme leaves. J Ethnopharmacol 2015;165:94-102. |
| 10. | Pang B, Xu X, Lu Y, Jin H, Yang R, Jiang C, et al. Prediction of new targets and mechanisms for quercetin in the treatment of pancreatic cancer, colon cancer, and rectal cancer. Food Funct 2019;10:5339-49. |
| 11. | Nan X, Su S, Ma K, Ma X, Wang X, Zhaxi D, et al. Bioactive fraction of Rhodiola algida against chronic hypoxia-induced pulmonary arterial hypertension and its anti-proliferation mechanism in rats. J Ethnopharmacol 2018;216:175-83. |
| 12. | Dorfmüller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003;22:358-63. |
| 13. | Anbara T, Sharifi M, Aboutaleb N. Endothelial to mesenchymal transition in the cardiogenesis and cardiovascular diseases. Curr Cardiol Rev 2019;16:306-314. |
| 14. | Madonna R, Cocco N, De Caterina R. Pathways and drugs in pulmonary arterial hypertension – Focus on the role of endothelin receptor antagonists. Cardiovasc Drugs Ther 2015;29:469-79. |
| 15. | Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 2012;122:4306-13. |
| 16. | Sesso HD, Gaziano JM, Jenkins DJ, Buring JE. Strawberry intake, lipids, C-reactive protein, and the risk of cardiovascular disease in women. J Am Coll Nutr 2007;26:303-10. |
| 17. | Cajigas HR, Awdish R. Classification and diagnosis of pulmonary hypertension. Heart Fail Rev 2016;21:229-37. |
| 18. | Crosswhite P, Sun Z. Molecular mechanisms of pulmonary arterial remodeling. Mol Med 2014;20:191-201. |
| 19. | Yildiz P. Molecular mechanisms of pulmonary hypertension. Clin Chim Acta 2009;403:9-16. |
| 20. | Li Q, Qiu Y, Mao M, Lv J, Zhang L, Li S, et al. Antioxidant mechanism of Rutin on hypoxia-induced pulmonary arterial cell proliferation. Molecules 2014;19:19036-49. |
| 21. | Fairlie-Jones L, Davison K, Fromentin E, Hill AM. The effect of anthocyanin-rich foods or extracts on vascular function in adults: A systematic review and meta-analysis of randomised controlled trials. Nutrients 2017;9:908. |
| 22. | Wei L, Deng W, Cheng Z, Guo H, Wang S, Zhang X, et al. Effects of hesperetin on platelet-derived growth factor-BB-induced pulmonary artery smooth muscle cell proliferation. Mol Med Rep 2016;13:955-60. |
| 23. | Luan Y, Chao S, Ju ZY, Wang J, Xue X, Qi TG, et al. Therapeutic effects of baicalin on monocrotaline-induced pulmonary arterial hypertension by inhibiting inflammatory response. Int Immunopharmacol 2015;26:188-93. |
| 24. | Li Q, Wang J, Zhu X, Zeng Z, Wu X, Xu Y, et al. Dihydromyricetin prevents monocrotaline-induced pulmonary arterial hypertension in rats. Biomed Pharmacother Biomed Pharmacother 2017;96:825-33. |
| 25. | Mialet-Perez J, Vindis C. Autophagy in health and disease: Focus on the cardiovascular system. Essays Biochem 2017;61:721-32. |
| 26. | Zhang S, Yang T, Xu X, Wang M, Zhong L, Yang Y, et al. Oxidative stress and nitric oxide signaling related biomarkers in patients with pulmonary hypertension: A case control study. BMC Pulmonary Med 2015;15:50. |
| 27. | Tabima D, Frizzell S, Gladwin M. Reactive oxygen and nitrogen species in pulmonary hypertension. Free Radical Biol Med 2012;52:1970-86. |
| 28. | Levy J, Towers C, Thorburn A. Targeting autophagy in cancer. Nature Rev. Cancer 2017;17:528-42. |
| 29. | Li XW, Wang XM, Li S, Yang JR. Effects of chrysin (5,7-dihydroxyflavone) on vascular remodeling in hypoxia-induced pulmonary hypertension in rats. Chin Med 2015;10:4. |
| 30. | Zhang Y, Cui Y, Deng W, Wang H, Qin W, Huang C, et al. Isoquercitrin protects against pulmonary hypertension via inhibiting PASMCs proliferation. Clin Exp Pharmacol Physiol 2017;44:362-370. |
| 31. | Dong F, Zhang J, Zhu S, Lan T, Yang J, Li L. Chrysin alleviates chronic hypoxia-induced pulmonary hypertension by reducing intracellular calcium concentration in pulmonary arterial smooth muscle cells. J Cardiovasc Pharmacol 2019;74:426-35. |
| 32. | Chiou C, Lin J, Kao P, Liu J, Cheng T, Chan P. Effects of hesperidin on cyclic strain-induced endothelin-1 release in human umbilical vein endothelial cells. Clin Exp Pharmacol Physiol 2008;35:938-43. |
| 33. | Morales-Cano D, Menendez C, Moreno E, Moral-Sanz J, Barreira B, Galindo P, et al. The flavonoid quercetin reverses pulmonary hypertension in rats. PLoS One 2014;9:e114492. |
| 34. | Voelkel N, Tamosiuniene R, Nicolls M. Challenges and opportunities in treating inflammation associated with pulmonary hypertension. Expert Rev Cardiovas Ther 2016;14:939-51. |
| 35. | Liu J, Hu S, Zhu B, Shao S, Yuan L. Grape seed procyanidin suppresses inflammation in cigarette smoke-exposed pulmonary arterial hypertension rats by the PPAR-γ/COX-2 pathway. Nutr Metab Cardiovasc Dis 2020;30:347-54. |
| 36. | Porto A, Palumbo R, Pieroni M, Aprigliano G, Chiesa R, Sanvito F, et al. Smooth muscle cells in human atherosclerotic plaques secrete and proliferate in response to high mobility group box1 protein. FASEB J 2006;20:2565-6. |
| 37. | Ranchoux B, Antigny F, Rucker-Martin C, Hautefort A, Péchoux C, Bogaard HJ, et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 2015;131:1006-18. |
| 38. | Zhang X, Liu Q, Zhang C, Sheng J, Li S, Li W, et al. Puerarin prevents progression of experimental hypoxia-induced pulmonary hypertension via inhibition of autophagy. J Pharmacol Sci 2019;141:97-105. |
| 39. | Demarco VG, Whaley-Connell AT, Sowers JR, Habibi J, Dellsperger KC. Contribution of oxidative stress to pulmonary arterial hypertension. World J Cardiol 2010;2:316-24. |
| 40. | Cassidy A, Mukamal KJ, Liu L, Franz M, Eliassen AH, Rimm EB. High anthocyanin intake is associated with a reduced risk of myocardial infarction in young and middle-aged women. Circulation 2013;127:188-96. |
| 41. | Rakotomalala G, Agard C, Tonnerre P, Tesse A, Derbré S, Michalet S, et al. Extract from Mimosa pigra attenuates chronic experimental pulmonary hypertension. J Ethnopharmacol 2013;148:106-16. |
| 42. | Shi R, Wei Z, Zhu D, Fu N, Wang C, Yin S, et al. Baicalein attenuates monocrotaline-induced pulmonary arterial hypertension by inhibiting vascular remodeling in rats. Pulm Pharmacol Ther 2018;48:124-35. |
| 43. | Almeida Rezende B, Pereira AC, Cortes SF, Lemos VS. Vascular effects of flavonoids. Curr Med Chem 2016;23:87-102. |
| 44. | Toh JY, Tan VM, Lim PC, Lim ST, Chong MF. Flavonoids from fruit and vegetables: A focus on cardiovascular risk factors. Curr Atheroscler Rep 2013;15:368. |
| 45. | Bondonno NP, Bondonno CP, Blekkenhorst LC, Considine MJ, Maghzal G, Stocker R, et al. Flavonoid-rich apple improves endothelial function in individuals at risk for cardiovascular disease: A randomized controlled clinical trial. Mol Nutr Food Res 2018;62:1700674. |
| 46. | Luís Â, Domingues F, Pereira L. Association between berries intake and cardiovascular diseases risk factors: A systematic review with meta-analysis and trial sequential analysis of randomized controlled trials. Food Funct 2018;9:740-57. |
| 47. | Cutler BR, Petersen C, Anandh Babu PV. Mechanistic insights into the vascular effects of blueberries: Evidence from recent studies. Mol Nutr Food Res 2017;61:1600271. |
| 48. | Jin H, Liu M, Zhang X, Pan J, Han J, Wang Y, et al. Grape seed procyanidin extract attenuates hypoxic pulmonary hypertension by inhibiting oxidative stress and pulmonary arterial smooth muscle cells proliferation. J Nutr Biochem 2016;36:81-8. |
| 49. | Guignabert C, Tu L, Le Hiress M, Ricard N, Sattler C, Seferian A, et al. Pathogenesis of pulmonary arterial hypertension: Lessons from cancer. Eur Respir Rev 2013;22:543-51. |
| 50. | Chang Z, Wang JL, Jing ZC, Ma P, Xu QB, Na JR, et al. Protective effects of isorhamnetin on pulmonary arterial hypertension: In vivo and in vitro studies. Phytother Res 2020;34:2730-44. |
| 51. | González JM, Briones AM, Starcher B, Conde MV, Somoza B, Daly C, et al. Influence of elastin on rat small artery mechanical properties. Exp Physiol 2005;90:463-8. |
| 52. | Liu P, Yan S, Chen M, Chen A, Yao D, Xu X, et al. Effects of baicalin on collagen I and collagen III expression in pulmonary arteries of rats with hypoxic pulmonary hypertension. Int J Mol Med 2015;35:901-8. |
| 53. | Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, et al. Right ventricular function and failure: Report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation 2006;114:1883-91. |
| 54. | Wang GY, McCloskey DT, Turcato S, Swigart PM, Simpson PC, Baker AJ. Contrasting inotropic responses to alpha1-adrenergic receptor stimulation in left versus right ventricular myocardium. Am J Physiol Heart Circ Physiol 2006;291:H2013-7. |
| 55. | Ahmed LA, Obaid AA, Zaki HF, Agha AM. Naringenin adds to the protective effect of L-arginine in monocrotaline-induced pulmonary hypertension in rats: Favorable modulation of oxidative stress, inflammation and nitric oxide. Eur J Pharm Sci 2014;62:161-70. |
| 56. | Nisbet R, Bland J, Kleinhenz D, Mitchell PO, Walp ER, Sutliff RL, et al. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am J Respir Cell Mol Biol 2010;42:482-90. |
| 57. | Dasgupta J, Kar S, Liu R, Joseph J, Kalyanaraman B, Remington SJ, et al. Reactive oxygen species control senescence-associated matrix metalloproteinase-1 through c-Jun-N-terminal kinase. J Cell Physiol 2010;225:52-62. |
| 58. | Pietta P. Flavonoids as antioxidants. J Natur Products 2000;63:1035-42. |
| 59. | Yuan T, Zhang H, Chen D, Chen Y, Lyu Y, Fang L, et al. Puerarin protects pulmonary arteries from hypoxic injury through the BMPRII and PPARγ signaling pathways in endothelial cells. Pharmacol Rep 2019;71:855-61. |
| 60. | Han X, Zhang Y, Zhou Z, Zhang X, Long Y. Hydroxysafflor yellow A improves established monocrotaline-induced pulmonary arterial hypertension in rats. J Int Med Res 2016;44:569-84. |
| 61. | Huertas A, Tu L, Humbert M, Guignabert C. Chronic inflammation within the vascular wall in pulmonary arterial hypertension: More than a spectator. Cardiovasc Res 2020;116:885-93. |
| 62. | Groth A, Vrugt B, Brock M, Speich R, Ulrich S, Huber L. Inflammatory cytokines in pulmonary hypertension. Respir Res 2014;15:47. |
| 63. | Chen F, Wang H, Yan J, Lai J, Cai S, Yuan L, et al. Grape seed proanthocyanidin reverses pulmonary vascular remodeling in monocrotaline-induced pulmonary arterial hypertension by down-regulating HSP70. Biomed Pharmacother Biomed Pharmacother 2018;101:123-8. |
| 64. | Inoue K, Kawahara K, Biswas K, Ando K, Mitsudo K, Nobuyoshi M, et al. HMGB1 expression by activated vascular smooth muscle cells in advanced human atherosclerosis plaques. Cardiovasc Pathol 2007;16:136-43. |
| 65. | Yang P, Kim D, Lee Y, Lee SE, Kang WJ, Chang HJ, et al. Glycyrrhizin, inhibitor of high mobility group box-1, attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling in rats. Respir Res 2014;15:148. |
| 66. | He Y, Cao X, Liu X, Xu Y, Liu J, Shi J, et al. Quercetin reverses experimental pulmonary arterial hypertension by modulating the TrkA pathway. Exper Cell Res 2015;339:122-34. |
| 67. | Zhang L, Pu Z, Wang J, Zhang Z, Hu D, Wang J. Baicalin inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation via the AKT/HIF-1α/p27-associated pathway. Int J Mol Sci 2014;15:8153-68. |
| 68. | Huang S, Chen P, Shui X, He Y, Wang H, Zheng J, et al. Baicalin attenuates transforming growth factor-β1-induced human pulmonary artery smooth muscle cell proliferation and phenotypic switch by inhibiting hypoxia inducible factor-1α and aryl hydrocarbon receptor expression. J Pharm Pharmacol 2014;66:1469-77. |
| 69. | Cai C, Xiang Y, Wu Y, Zhu N, Zhao H, Xu J, et al. Formononetin attenuates monocrotalineinduced pulmonary arterial hypertension via inhibiting pulmonary vascular remodeling in rats. Mol Med Rep 2019;20:4984-92. |
| 70. | Matori H, Umar S, Nadadur RD, Sharma S, Partow-Navid R, Afkhami M, et al. Genistein, a soy phytoestrogen, reverses severe pulmonary hypertension and prevents right heart failure in rats. Hypertension 2012;60:425-30. |
| 71. | Stolz A, Ernst A, Dikic I. Cargo recognition and trafficking in selective autophagy. Nature Cell Biol 2014;16:495-501. |
| 72. | Sasaki Y, Ikeda Y, Iwabayashi M, Akasaki Y, Ohishi M. The impact of autophagy on cardiovascular senescence and diseases. Int Heart J 2017;58:666-73. |
| 73. | Kotawong K, Chaijaroenkul W, Muhamad P, Na-Bangchang K. Cytotoxic activities and effects of atractylodin and β-eudesmol on the cell cycle arrest and apoptosis on cholangiocarcinoma cell line. J Pharmacol Sci 2018;136:51-6. |
| 74. | Long L, Yang X, Southwood M, Lu J, Marciniak SJ, Dunmore BJ, et al. Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation. Circulation Res 2013;112:1159-70. |
| 75. | Shi R, Zhu D, Wei Z, Fu N, Wang C, Liu L, et al. Baicalein attenuates monocrotaline-induced pulmonary arterial hypertension by inhibiting endothelial-to-mesenchymal transition. Life Sci 2018;207:442-50. |
| 76. | Huang S, Zhu X, Huang W, He Y, Pang L, Lan X, et al. Quercetin inhibits pulmonary arterial endothelial cell transdifferentiation possibly by Akt and Erk1/2 pathways. Bio Med Res Int 2017;2017:6147294. |
| 77. | Wideman R, Hamal K. Idiopathic pulmonary arterial hypertension: An avian model for plexogenic arteriopathy and serotonergic vasoconstriction. J Pharmacol Toxicol Methods 2011;63:283-95. |
| 78. | Gao Y, Chen T, Raj J. Endothelial and smooth muscle cell interactions in the pathobiology of pulmonary hypertension. Am J Respir Cell Mol Biol 2016;54:451-60. |
| 79. | Jiang Y, Yang Y. Trifolium pratense isoflavones improve pulmonary vascular remodelling in broiler chickens. J Anim Physiol Anim Nutr 2016;100:1159-68. |
| 80. | Kuriyama S, Morio Y, Toba M, Nagaoka T, Takahashi F, Iwakami S, et al. Genistein attenuates hypoxic pulmonary hypertension via enhanced nitric oxide signaling and the erythropoietin system. Am J Physiol 2014;306:L996-1005. |
| 81. | Wang L, Wang Y, Lei Z. Chrysin ameliorates ANTU-induced pulmonary edema and pulmonary arterial hypertension via modulation of VEGF and eNOs. J Biochem Mol Toxicol 2019;33:E22332. |
| 82. | Rowlands D. Mitochondria dysfunction: A novel therapeutic target in pathological lung remodeling or bystander? Pharmacol Ther 2016;166:96-105. |
| 83. | Piantadosi C, Suliman H. Mitochondrial dysfunction in lung pathogenesis. Ann Rev Physiol 2017;79:495-515. |
| 84. | Kasahara A, Scorrano L. Mitochondria: From cell death executioners to regulators of cell differentiation. Trends Cell Biol 2014;24:761-70. |
| 85. | He Y, Fang X, Shi J, Li X, Xie M, Liu X. Apigenin attenuates pulmonary hypertension by inducing mitochondria-dependent apoptosis of PASMCs via inhibiting the hypoxia inducible factor 1α-KV1.5 channel pathway. Chem Biol Interact 2020;317:108942. |
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