Artemisinin and Its Derivate Alleviate Pulmonary Hypertension and Vasoconstriction in Rodent Models

Abstract

Background. Pulmonary arterial hypertension (PAH) is a complex pulmonary vasculature disease characterized by progressive obliteration of small pulmonary arteries and persistent increase in pulmonary vascular resistance, resulting in right heart failure and death if left untreated. Artemisinin (ARS) and its derivatives, which are common antimalarial drugs, have been found to possess a broad range of biological effects. Here, we sought to determine the therapeutic benefit and mechanism of ARS and its derivatives treatment in experimental pulmonary hypertension (PH) models. Methods. Isolated perfused/ventilated lung and isometric tension measurements in arteries were performed to test pulmonary vasoconstriction and relaxation. Monocrotaline (MCT) and hypoxia+Su5416 (SuHx) were administered to rats to induce severe PH. Evaluation methods of ARS treatment and its derivatives in animal models include echocardiography, hemodynamics measurement, and histological staining. In vitro, the effect of these drugs on proliferation, viability, and hypoxia-inducible factor 1α (HIF1α) was examined in human pulmonary arterial smooth muscle cells (hPASMCs). Results. ARS treatment attenuated pulmonary vasoconstriction induced by high K+ solution or alveolar hypoxia, decreased pulmonary artery (PA) basal vascular tension, improved acetylcholine- (ACh-) induced endothelial-dependent relaxation, increased endothelial nitric oxide (NO) synthase (eNOS) activity and NO levels, and decreased levels of NAD(P)H oxidase subunits (NOX2 and NOX4) expression, NAD(P)H oxidase activity, and reactive oxygen species (ROS) levels of pulmonary arteries (PAs) in MCT-PH rats. NOS inhibitor, L-NAME, abrogated the effects of ARS on PA constriction and relaxation. Furthermore, chronic application of both ARS and its derivative dihydroartemisinin (DHA) attenuated right ventricular systolic pressure (RVSP), Fulton index (right ventricular hypertrophy), and vascular remodeling of PAs in the two rat PH models. In addition, DHA inhibited proliferation and migration of hypoxia-induced PASMCs. Conclusions. In conclusion, these results indicate that treatment with ARS or DHA can inhibit PA vasoconstriction, PASMC proliferation and migration, and vascular remodeling, as well as improve PA endothelium-dependent relaxation, and eventually attenuate the development and progression of PH. These effects might be achieved by decreasing NAD(P)H oxidase generated ROS production and increasing eNOS activation to release NO in PAs. ARS and its derivatives might have the potential to be novel drugs for the treatment of PH.

Effect of blood flow restriction training on health promotion in middle-aged and elderly women: a systematic review and meta-analysis

“…American Heart Association (AHA) and global healthcare practitioners recognize elevated SBP and DBP are among the risk factors of developing cardiac artery diseases (CAD) and cardiovascular diseases (CVD) ( Price et al, 2019 ; Naidu et al, 2022 ; Kittleson et al, 2023 ). In this study, it can be observed that blood flow restriction training intervention has beneficial effect on the regulation of blood pressure, especially through down-regulating SBP, probably through enhancing eNOS synthesis and promoting the secretion of nitric oxide (NO) to the blood vessels smooth muscle endothelial cells ( Li et al, 2020 ; Bao et al, 2022 ; Cai and Chen, 2022 ; Wu et al, 2022 ). Therefore, it is recommended for the elderly to practice blood flow restriction training under appropriate workload, which can be helpful in maintaining their regular blood pressure and have potential benefits in decreasing CAD and CVD risk factors.…”

Upregulated expression of a TOR2A gene product‐salusin‐β in the paraventricular nucleus enhances sympathetic activity and cardiac sympathetic afferent reflex in rats with chronic heart failure induced by coronary artery ligation

“…The myocyte cross‐sectional area in the LV lateral‐mid free wall, including epicardial and endocardial layers, was ascertained in H&E‐stained histological images using Image‐Pro Plus 6.0 software 52 . Myocardial and perivascular fibrosis were detected in the sections with Masson's trichrome staining, and the blue collagen deposition area/total cross‐sectional area of the myocardium (%) was calculated as previously reported 48,53,54 …”

“…48,53,54 4 12. | Materials Apocynin (APO), diethyldithiocarbamic acid (DETC), dimethyl sulfoxide (DMSO), N′-nitro-L-arginine-methyl ester hydrochloride (L-NAME), N-acetyl-L-cysteine (NAC), and tempol were purchased from Sigma Chemical Co. Salusin-β peptide was synthesized by Shanghai Changxi Biological Technology Co., Ltd. Anti-salusin-β antibody was obtained from Cloud-clone, and control IgG antibody was provided by Proteintech.…”

Novel artemisinin derivative P31 inhibits VEGF-induced corneal neovascularization through AKT and ERK1/2 pathways

“…In recent years, its anti-angiogenic effects have attracted much attention. Various models have accumulated mounting evidence, demonstrating the involvement of inhibiting aberrant angiogenesis and corneal neovascularization in the actions of artemisinin and its derivatives [ [21] , [22] , [23] , [24] ]. Artemisinin reduced the proliferation, migration, and tube formation of HUVEC, as well as the expression of VEGFR1 and VEGFR2 [ 24 ].…”