Background
Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure ≥20 mmHg when diagnosed with right heart catheterisation, [1] or a right ventricular systolic pressure ≥40 mmHg (in the absence of pulmonary stenosis and acute right heart failure) as measured with transthoracic echocardiography. [2] Approximately 75 million people suffer from PH globally, [3] and it occurs mainly in women. [4] It is associated with several conditions, such as HIV, left heart disease, schistosomiasis, chronic obstructive pulmonary disease and tuberculosis sequelae. [5 – 7] These conditions increase pulmonary vascular remodelling that results in increased pulmonary vasculature resistance and therefore PH. The current PH treatment regimens have made a significant clinical impact, as they improve clinical outcomes and quality of life to a certain degree. [1] However, they do not cure PH, suggesting that its pathophysiology is not fully understood, [8] and this limited impact of the current drugs on PH highlights a need for better treatment regimens. During the past 5 years, and particularly in the post-COVID-19 period, drug repurposing has been proposed as a novel way to augment the health benefits afforded by current PH drugs. [9] The articles on this topic are too many to list in full, but these three show the importance of the idea. [10 – 12]
A brief overview of the pathophysiology and treatment of PH
PH has a complex pathophysiology that includes an array of molecular factors and proteins that trigger myriad molecular pathways [13] such as increased proliferation of pulmonary artery smooth-muscle cells (PASMCs) and a cancer-like phenotype characterised by PASMC resistance to apoptosis and excessive proliferation of pulmonary artery endothelial cells (PAECs). [14] Other pathways include pulmonary inflammation, elevated oxidative stress, lung mitochondrial dysfunction, lung fibrosis and pulmonary vasoconstriction. [14] These pathways ultimately result in obliterative changes to the pulmonary arterioles, including thickening of the intima and medial layers [13] and plexogenic arteriopathy. [15]
Treatment options for PH improve PH-related symptoms by targeting these molecular pathways. Drugs include endothelin-1 receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin analogues and prostacyclin receptor agonists. [16] PH survival without treatment used to average 2.8 years, with survival rates of 68%, 48% and 34% at 1, 3 and 5 years after diagnosis, respectively. [17] However, with treatment, survival rates have improved to 97.2%, 91.5%, 84.2%, 80.2% and 75.9% at 1, 2, 3, 4 and 5 years, respectively. [18] Great strides have therefore been made with regard to PH treatment, but there is room for improvement, as despite these drugs, patients still die from PH. This situation suggests that there is a need for better treatment strategies. [19]
Drug repurposing in PH
The aim of drug repurposing [20] in PH is to reutilise drugs that were traditionally used for other diseases in the hope that they may provide health benefits for PH patients too. Accumulating literature suggests that there is indeed an instrumental role for drug repurposing in PH. For instance, imatinib, a tyrosine kinase inhibitor used in patients with chronic myelogenous leukaemia, [21] has been shown to have vasodilatory properties by blocking the platelet-derived growth factor-activated pathway of vascular remodelling. [22] It can therefore be linked to PH, which develops through a similar mechanism. [23] As a result, imatinib was repurposed for PH and has been shown to improve haemodynamics and pulmonary vascular resistance in PH patients. [24] Other examples are summarised in Table 1 .
Table 1
A list of pharmaceutical drugs used for other diseases that could be repurposed for PH (some have recently been tested in a PH context)
PH = pulmonary hypertension FoxO1 = forkhead box protein O1
| Drug | Approved for | Effects in models of PH | References |
| Imatinib | Chronic myeloid leukaemia | Improves haemodynamics and exercise capacity | Frost et al. [24] |
| Tacrolimus | Solid-organ transplantation | Improves BMPR2 expression in peripheral blood mononuclear cells of human subjects | Spiekerkoetter et al. [25] |
| Anastrozole | Breast cancer | Improves 6-minute walk distance and reduces 17β-oestradiol levels | Kawut et al. [26] |
| Paclitaxel | Ovarian cancer | Inhibits pulmonary vascular remodelling by FoxO1-mediated autophagy suppression | Feng et al., [27] Zhao et al. [28] |
| Etanercept | Rheumatoid arthritis | Prevents and reverses monocrotaline-induced PH by reducing inflammatory cell infiltration | Zhang et al. [29] |
| Carvedilol | Congestive heart failure | Reduces right ventricular systolic pressures in patients | Cheong et al. [30] |
| Melatonin | Jet lag | Improves cardiac function, reduces oxidative stress, enhances antioxidant systems, and inhibits pulmonary vascular remodelling | Hung et al., [31] Maarman et al., [32] Wang et al. [33] |
| Hydroxychloroquine | Malaria | Attenuates PH by decreasing proliferation and increases apoptosis of pulmonary artery smooth-muscle cells in pulmonary hypertensive arteries. | Ryan [34] |
| Anakinra | Rheumatoid arthritis | Reduces inflammation and right ventricular dysfunction in PH via interleukin signalling | Trankle et al. [35] |
| Rituximab | Non-Hodgkin’s lymphoma | Improves 6-minute walk distance | Zamanian et al. [36] |
| Sotatercept | Chemotherapy-induced anaemia, multiple myeloma, beta-thalassaemia, and end-stage kidney disease | Improves pulmonary vascular resistance in patients, and reduced N-terminal pro-B-type natriuretic peptide levels | Humbert et al. [37] |
| Dimethyl fumarate | Multiple sclerosis | Improves PH by blocking proinflammatory pathways and reducing the infiltration of immune cells in lung tissue. | Grzegorzewska et al. [38] |
| Fasudil | Angina and cerebral vasospasm | Reduces pulmonary vascular resistance in PH patients | Fujita et al., [39] Fukumoto et al. [40] |
| Nesiritide | Acute decompensated heart failure | Ameliorates pulmonary capillary wedge pressure | Michaels et al. [41] |
Repurposing from an African perspective
Most Africans rely on medicinal plants as a source of healthcare. [42] The World Health Organization reports that ~80% of developing countries depend largely on medicinal plants for the treatment of ailments and diseases. [43] Over the years, African traditional plants have received attention for their health benefits, a characteristic that is attributed to their high polyphenol content. [44] There has been a close to 60% increase in the number of research outputs based on the potential health benefits of African medicinal plants in the past decade. [45]
Many of these African medicinal plants have beneficial effects against diseases such as cancer, [46] diabetes, [47] inflammation [48] and bacterial respiratory diseases. [49] However, there is a paucity of studies investigating the potential of African medicinal plants in counteracting PH, and this is a pity, as these plants offer a niche for the discovery of novel therapeutic targets or adjunct therapies for PH. Such discoveries could equate to afforable therapies to assist PH patients in resource-limited developing-world settings. PH drugs are expensive and therefore inaccessible to many patients in developing countries, where most public health healthcare systems cannot afford to foot the high costs of pharmaceutical drugs. There is therefore a continued search for adjunct PH therapies that are effective and affordable. [50] For this purpose, few studies have investigated natural products or traditional herbs as an adjunct therapeutic approach in PH. [51 – 53] Some medicinal plants from India and Asia show considerable benefit against key aspects of PH pathophysiology, [51 – 53] but there is a paucity of such studies on African medicinal plants and PH. This is strange, as Africa boasts rich biodiversity and a wide range of plant species that have medicinal properties. We perused the literature for studies that have demonstrated the underlying mechanisms of these African medicinal plants, and we review whether they counteract molecular pathways in other diseases that are also involved in the pathogenesis of PH. We propose that these African medicinal plants could be used against PH and that this may also be observed as a form of ‘drug’ repurposing. Needless to say, more research is warranted.
Anti-inflammatory effects of African medicinal plants
Inflammation is usually triggered by damage to living tissues resulting from microbial infections, physical damage or defective immune responses. [54] Various mechanisms of action have been proposed to explain the anti-inflammatory activity of medicinal plants. These mechanisms include inhibition of 15-lipoxygenases, [55] elevation of nitric oxide (NO) production, [57] inhibition of phospholipase A 2 , [56] and modulation of proinflammatory gene expression. [57] African medicinal plants have become synonymous with anti-inflammatory effects; [48] in fact, Aspalathus linearis (also known as rooibos) is a unique South African species that is considered a potent anti-inflammatory agent. Studies have shown that it achieves this action by limiting the cellular release of proinflammatory cytokines (tumour necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and interleukin 6 (IL-6)) in lipopolysaccharide-induced inflammation. [58 , 59] Similar effects have been shown with the African potato in a rat model of diclofenac induced inflammation [60] (Table 2) .
Table 2
African medicinal plants (tested in non-PH models) with anti-inflammatory activity that could be repurposed for PH
PH = pulmonary hypertension iNOS = inducible nitric oxide synthase NF-κB = nuclear factor kappa B TNF-α = tumour necrosis factor alpha IL-1β = interleukin 1 beta IL-6 = interleukin 6
| Plant | Common name | Experimental model | Mechanism | References |
| Hypoxis hemerocallidea | African potato | Diclofenac-induced inflammation animal model of rats | Inhibition of iNOS and NF-κB | Ojewole [60] |
| In vitro model | Zulfiqar et al. [61] | |||
| Aspalathus linearis | Rooibos tea | Lipopolysaccharide-induced inflammation animal model of mice | Inhibition of proinflammatory cytokines (TNF-α, IL-1β and IL-6) | Ajuwon et al., [58] Lee and Bae [59] |
| In vitro model | Lee and Bae [59] | |||
| Ximenia caffra | Large sourplum | In vitro model | Inhibits the messenger RNA expression of proinflammatory genes (IL-6, iNOS and TNF-α) | Zhen et al. [62] |
| Asparagus africanus | Wild asparagus | Carrageenan-induced rat paw oedema and inflammation in Swiss albino and Wistar rats | Inhibition of inflammation by limiting proinflammatory cytokines | Ojewole [60] |
| Aloe ferox | Aloe | Carrageenan-induced rat paw oedema and inflammation | Inhibition of inflammation due to a high content of malic acid acylated carbohydrates | Mwale and Masika [63] |
Antioxidant properties of African medicinal plants
African medicinal plants are well known for their ability to scavenge free radicals and activate cell antioxidant defence systems. [64] Their mechanism of action is complex, but reactive oxygen species (ROS) stimulate the translocation of nuclear respiratory factor 2 (Nrf 2) to the nucleus, where it binds to antioxidant response element motifs to enhance redox defence [65] and the elevation of intracellular antioxidant gene and protein expression, as well as the increase of antioxidant enzyme activities. [66] Several African medicinal plants can counteract the deleterious effects of elevated oxidative damage to cell structures, including lipids, proteins and DNA. Aloe claviflora is a plant that can scavenge ROS and limit lipid peroxidation, [67] while Aloe vera and Aspalathus linearis induce antioxidant effects via the Nrf-2 pathway (Table 3) .
Table 3
African medicinal plants could be repurposed for PH owing to their highly relatable mechanisms of actions against pathways that are key to PH pathogenesis
PH = pulmonary hypertension Nrf-2 = nuclear respiratory factor 2 H2O2 = hydrogen peroxide HO-1 = haem oxygenase 1 LPS = lipopolysaccharide ROS = reactive oxygen species
| Plant | Common name | Experimental model | Mechanism | References |
| Dacryodes edulis | Safou plum | Fructose-STZ diabetes induced rat model | Suppresses the expression of Nrf-2 to induce antioxidant activity | Erukainure et al. [74] |
| Moringa oleifera | Drumstick tree or moringa | In vitro model | Suppresses H2O2-induced mitochondrial depolarisation and apoptosis through suppression of the mitochondrial-mediated apoptosis pathway, while it activates the Nrf-2/HO-1 signalling pathway | Kirindage et al. [75] |
| Lipopolysaccharide-induced inflammation model in mice | Decreased mitochondrial superoxide content, and restoration of the mitochondrial membrane potential in the LPS-induced macrophages | Sailaja et al. [76] | ||
| Aloe vera | Aloe | In vitro model | Attenuates oxidative stress, initiates antioxidant defences, regulates mitochondrial dysfunction and suppresses apoptosis | Xu et al. [77] |
| Aloe claviflora | Aloe | In vitro model | Inhibits lipid peroxidation and has ROS scavenging effects | Lindsey et al. [67] |
Close to 90% of cellular ROS is produced by mitochondria, [68] while the same organelles are key role players in the optimal function of cellular antioxidant systems. [69] In the absence of proper mitochondrial regulation, antioxidant capacity is reduced, which leads to the excessive production of ROS that further impair mitochondrial function. [70] A. vera has been shown to improve mitochondrial function by reducing ROS production, while Moringa oleifera can do the same via an Nrf2/haem oxygenase 1 (HO-1) signalling pathway (Table 3) . Mitochondrial dysfunction is considered a key component of PH that occurs specifically in PASMCs and PAECs. [71] Potent antioxidants [32 , 72] that could improve mitochondrial function and mitochondrial regulation have previously been highlighted as therapeutic targets for PH by our group. [13 , 73] It therefore follows that African medicinal plants may be able to show benefit in PH models by reducing ROS production, limiting oxidative stress and improving mitochondrial function.
Antiprolific effects of African medicinal plants
African medicinal plants have potent antiprolific effects in a wide range of experimental models. [78] A root bark extract of Zanthoxylum paracanthum was tested in human breast cancer (HCC1395) and human prostate cancer (DU145) cell lines, where it showed antiprolific activity, [79] but the mechanisms remain poorly understood. The African cherry has demonstrated antiprolific activity in human prostate cancer cells, which is believed to be mediated via reduced apoptosis. [80] Other plants that have similar effects include Zingiber ocianale and Sutherlandia frutescens in human cancer cell lines [81 – 82] (Table 4) .
Table 4
African medicinal plants (tested in non-PH models) with antiprolific and apoptosis activity for smooth-muscle cell remodelling that could be repurposed for PH
PH = pulmonary hypertension.
| Plant | Common name | Experimental model | Mechanism | References |
| Curculigo orchioides Gaertn | Golden eye grass or black musli | In a human breast cancer cell line (MCF-7) | Induced anti-cancer effects by increasing cell death of cancer cells | Singh [86] |
| Sutherlandia frutescens | Cancer bush | LS180 colorectal cancer mini-tumours | Induced anti-cancer effects by limiting cancer cell metabolism | Gouws et al. [81] |
| Fagaropsis angolensis | Murumu or dale | Throat and colon cancer cell lines (Hep2 and CT-26.CL-25) | Induced antiprolific effects via the actions of polyphenols | Gaobotse et al. [87] |
| Zanthoxylum paracanthum | Kokwaro (Rutaceae) | Cancer cell lines (HCC1395, DU145, Vero E6) | Induced antiprolific activity | Kaigongi et al. [79] |
| Prunus africana | African cherry | Human prostate cancer cells (PC3) | Induced antiprolific activity possibly mediated via an increase in apoptosis | Komakech et al. [80] |
In PH, proliferation is a key feature that leads to pulmonary arteriolar remodelling, [83] and because PASMCs and PAECs become resistant to apoptosis, PH has been deemed to have a cancer-like phenotype. [84] Furthermore, impaired apoptosis regulation in these cells is also a major determinant of PASMC proliferation in remodelling. [85] There are myriad mechanisms outside the scope of this review, but impaired apoptosis regulation and cell metabolism are instrumental. Given the evidence that African medicinal plants can induce antiprolific effects, it is therefore likely that that they may also provide benefit against the cancer-like phenotype observed in PH.
African medicinal plants that have been tested in models expressing features of PH
Some African medicinal plants have been reported to induce therapeutic effects either in PH models or in experimental models that express certain key features of PH, including right ventricular hypertrophy, lung fibrosis, pulmonary inflammation, pulmonary artery vasoconstriction and endothelial cell proliferation (Table 5) . These plants can reduce inflammation in PH models by decreasing inflammation factors such as nuclear factor kappa B (NF-κB), TNF-α, and type 1 and type 2 T-helper (Th1 and Th2) cytokines. [88] African medicinal plants have polyphenols that give these plants the ability to counteract the features listed here, through potent antioxidant actions. Some of these plants can increase antioxidant enzyme activities of superoxide dismutase, catalase and glutathione peroxidase, while others can regulate mitochondrial function as a means to limiting ROS production. [89 , 90] Other plants induce vascular relaxation by increasing NO and endothelial NO synthase expression (Table 5) . Extracts of these plants have also been reported to counteract vascular remodelling in PH models, doing so by suppressing epithelial-mesenchymal transition through the transforming growth factor beta 1 (TGF-β1)/Smad pathway, [91] which decreases the expression of p38 mitogen-activated protein [92] and causes reduction of endothelin 1. [93]
Table 5
A list of African medicinal plants that have demonstrated to have therapeutic actions in models that express features of PH
PH = pulmonary hypertension NADPH = nicotinamide adenine dinucleotide phosphate NO = nitric oxide Ca2+ = calcium ions eNOS = endothelial nitric oxide synthase NF-κB = nuclear factor kappa B Nrf2 = nuclear respiratory factor 2 Th1 = type 1 T-helper Th2 = type 2 T-helper EMT = epithelial-mesenchymal transition TGF-β1 = transforming growth factor beta 1
| Plant | Experimental model of PH | Mechanism | References |
| Terminalia arjuna | Monocrotaline-induced PH rat model | Reduces right ventricle hypertrophy and medial wall thickness of pulmonary arteries through the decrease of lipid peroxidation, and NADPH oxidases protein expression in the lung and increases superoxide dismutase and catalase activity | Kapoor et al., [94] Pawar and Bhutani [95] |
| Moringa oleifera Lam. | Monocrotaline-induced PH rat model | Increases superoxide dismutase levels | Chen et al. [96] |
| Securigera securidaca L. | Broiler chicken reared at high altitude | Prevents the inactivation of NO through scavenging of superoxide ions | Ahmadipour [97] |
| Allium sativium (garlic) | Acute hypoxic pulmonary vasoconstriction | Increases the action of endothelial NO synthase, thereby relaxing the vascular smooth muscles | Fallon et al. [98] |
| Allium macrostemon Bunge | Isolated pulmonary artery | Initiates Ca2+/protein kinase A and endothelial NO synthase signalling pathway in endothelial cells | Han et al. [99] |
| Trifolium pratense L. | Broiler chicken reared at high altitude | Increases NO synthase secretion | Jiang and Yang [93] |
| Mimosa pigra L. | Hypoxia-induced PH in rats | Elevates NO production and decreases pulmonary artery pressure in hypoxia-induced PH | Rakotomalala et al. [92] |
| Centella asiatica | Hypoxia-induced PH in rats | Activates the NO‑mediated signals by enhancing the phosphorylation of serine/threonine‑specific protein kinase/eNOS, thus promoting NO production and protecting endothelial cells from hypoxia‑induced apoptosis | Wang et al. [100] |
| Acacia senegal | Waterpipe smoke exposure | Prevents pulmonary inflammation and DNA damage, and restores the impairment of lung function via prevention of expression of NF-κB that induced an overexpression of Nrf2 in mice | Nemmar et al. [101] |
| Artemisia herba-alba Asso. | Broiler chicken | Down-regulates and up-regulates Th1 and Th2 cytokines, respectively, in chronic multisystemic inflammation in Algerian patients | Messaoudene et al. [88] |
| Trifolium pratense L. | Broiler chicken | Reduces endothelin 1 in lung tissues | Jiang and Yang [93] |
| Mimosa pigra L. | Hypoxia-induced PH in rats | Decreases the expression of p38 mitogen-activated protein, thus ameliorating the proliferative endothelial cells of the lung tissue in rats | Rakotomalala et al. [92] |
| Aloe ferox | Paraquat-induced pulmonary fibrosis in mice | Attenuates pulmonary fibrosis by suppressing the EMT process through the TGF-β1/Smads/p38 pathway | Zhang et al. [91] |
Challenges and recommendations
Several challenges exist concerning the use of medicinal plants for the treatment of human diseases. It must be acknowledged that African medicinal plants often have pleiotropic effects, [102] and establishing a single mechanism is difficult. Other challenges include poor bioavailability, [103] nonspecific or pleiotropic actions, [42] mitohormesis, [104] drug interactions, [105] and poor pharmacokinetics [106] and lack of accurate/effective dosage and dose conversion from experimental studies to human trials. [107 , 108] However, great advances have been made in trying to overcome these challenges in experimental studies or clinical trials, such as the use of inductively coupled plasma-optical emission spectrophotometry [103] and nanoparticles [109] to improve, for example, bioavailability. The latter has had considerable success in previous studies. A point of caution is needed here, as conventional methods of nanoparticle production use polyvinyl alcohol, polyethylene glycol, and D-alpha tocopheryl polyethylene glycol 1000 succinate as stabilisers during synthesis. However, these are toxic, and researchers have been searching for stabilisers that are non-toxic. Studies have shown that plant extracts can also be used as stabilisers for the fabrication of stable poly (lactide-co-glycolide) nanoparticles. [110] We recommend that future studies test poly (lactide-co-glycolide) nanoparticles that have been enriched with a medicinal plant extract to enhance cellular uptake and increase bioactivity. [111] Most medicinal plants or herbs contain several bioactive compounds, [112] making it difficult to know which compounds in an extract have been loaded onto the nanoparticle, so it may be challenging to ensure consistent experimental outcomes across studies. We are of the opinion that where all or most of the individual compounds in an extract have been successfully captured onto nanoparticles, it may still provide significant health benefits or remarkably improve the actions of nanoparticles. [113 , 114]
Conclusion
Drug repurposing offers a relatively novel approach to achieving better treatment outcomes in PH. Drugs that could be repurposed for PH include melatonin, anakinra, rituximab and nesiritide. African medicinal plants also have potential as adjuvant therapies for PH, as they have been reported to have few to no side-effects and the ability to counteract instrumental pathways or vascular remodelling, which makes them attractive therapeutic targets for PH. They may improve the quality of life of patients suffering from PH and could offer an affordable adjuvant in resource-limited settings. Viable options include A. linearis, Allium sativium, Trifolium pratense L., Mimosa pigra L. and Aloe ferox . However, the majority of these plants have never been tested in an experimental PH model, so our proposition is hypothetical at best. Regardless, we believe that future studies should investigate these and other African medicinal plants in appropriate models of PH, to test their efficacy and effectiveness. Perhaps one day we will be able to put Africa’s diverse flora to good use in PH research.
Footnotes
All authors meet the criteria to qualify as authors, have contributed significantly and equally to the manuscript, and have seen/approved the final version of the manuscript.
Special thanks and appreciation to the Faculty of Medicine and Health Sciences at Stellenbosch University, the National Research Foundation of South Africa, the South African Medical Research Council, the South African Rooibos Council, and the Harry Crossley Foundation of South Africa.
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