Astragaloside IV blocks monocrotaline‑induced pulmonary arterial hypertension by improving inflammation and pulmonary artery remodeling

Abstract

Pulmonary arterial hypertension (PAH) is associated with increased inflammation and abnormal vascular remodeling. Astragaloside IV (ASIV), a purified small molecular saponin contained in the well-know herb, Astragalus membranaceus , is known to exert anti-inflammatory and anti-proliferation effects. Thus, the present study investigated the possible therapeutic effects of ASIV on monocrotaline (MCT)-induced PAH. Rats were administered a single intraperitoneal injection of MCT (60 mg/kg), followed by treatment with ASIV at doses of 10 and 30 mg/kg once daily for 21 days. Subsequently, right ventricle systolic pressure, right ventricular hypertrophy and serum inflammatory cytokines, as well as pathological changes of the pulmonary arteries, were examined. The effects of ASIV on the hypoxia-induced proliferation and apoptotic resistance of human pulmonary artery smooth muscle cells (HPASMCs) and the dysfunction of human pulmonary artery endothelial cells (HPAECs) were evaluated. MCT elevated pulmonary artery pressure and promoted pulmonary artery structural remodeling and right ventricular hypertrophy in the rats, which were all attenuated by both doses of ASIV used. Additionally, ASIV prevented the increase in the TNF-α and IL-1β concentrations in serum, as well as their gene expression in lung tissues induced by MCT. In in vitro experiments, ASIV attenuated the hypoxia-induced proliferation and apoptotic resistance of HPASMCs. In addition, ASIV upregulated the protein expression of p27, p21, Bax, caspase-9 and caspase-3, whereas it downregulated HIF-1α, phospho-ERK and Bcl-2 protein expression in HPASMCs. Furthermore, in HPAECs, ASIV normalized the increased release of inflammatory cytokines and the increased protein levels of HIF-1α and VEGF induced by hypoxia. On the whole, these results indicate that ASIV attenuates MCT-induced PAH by improving inflammation, pulmonary artery endothelial cell dysfunction, pulmonary artery smooth muscle cell proliferation and resistance to apoptosis.

Protective effects of astragaloside IV against hypertension-induced vascular remodeling involves the DNMT1 and TET2 signaling pathway

“…Consistent with our findings, a recent study demonstrated that AS-IV reduced blood pressure in rats fed with a high-fat diet [33]. AS-IV has been also found to attenuate pulmonary artery pressure induced by hypoxia or monocrotaline as well as pulmonary artery structural remodeling [25,26,34,35]. The decrease in blood pressure can be associated with vascular relaxation mediated by AS-IV.…”

“…Previous studies reported that AS-IV inhibited the proliferation and migration of VSMCs stimulated with high glucose or angiotensin II (Ang II), a vasoconstrictor that induces growth of VSMCs by acting on the AT1 receptor [23,24]. Recent studies have reported that AS-IV protects against vascular remodeling induced by hypoxia and monocrotaline [25,26]. An early study showed that AS-IV relaxed the aorta of spontaneous hypertensive rats through endothelium-dependent and endothelium-independent ways [27].…”

Dapagliflozin reduces the vulnerability of rats with pulmonary arterial hypertension-induced right heart failure to ventricular arrhythmia by restoring calcium handling

“…Rats (n = 8 per group) were anaesthetised intraperitoneally with pentobarbital sodium (40 mg/kg) and heparinised with heparin sodium (400 U). As previously described [ 18 , 19 ], measurement of pulmonary arterial pressure (PAP) and right ventricular pressure (RVP) was performed in rat hearts by using a heparin-saline fluid-filled polyethylene (PE) catheter. Briefly, the right jugular vein was separated, and a 2F PE catheter transducer was then inserted into the pulmonary artery (PA) through the right atrium and the RV.…”

Antihypertension effect of astragaloside IV during cerebral ischemia reperfusion in rats

“…It has the effects of improving immunity, reducing stress reaction, antivirus, anti-inflammation, analgesia, organ protection and promoting metabolism ( 31 , 32 ). In addition, astragaloside IV has the effect of regulating blood pressure ( 35 , 36 ).…”

“…According to the data provided by Traditional Chinese Medicine Systems Pharmacology database and analysis platform, astragaloside IV is BBB non-penetrable, which may have limited effect on the central nervous system. It has been reported that astragaloside IV relieved hypertension via improving inflammation, pulmonary artery remodelling and oxidative stress ( 35 , 36 ). Then the decrease of NKCC1 expression may be due to the stable blood pressure after CIR that led to the reduction of AVP demand.…”