Tsantan Sumtang Alleviates Chronic Hypoxia-Induced Pulmonary Hypertension by Inhibiting Proliferation of Pulmonary Vascular Cells

Abstract

Hypoxia-induced pulmonary hypertension (HPH) is a severe condition associated with significant morbidity and mortality in people living at high altitude. Tsantan Sumtang, a traditional Tibetan medicine, has been routinely used for the treatment of cardiopyretic disease, as well as stenocardia. Interestingly, our previous research found that Tsantan Sumtang improved HPH in rats maintaining in a hypobaric chamber. We performed a series of experiments to test the indexes of vasoconstriction and vascular remodeling, the key pathophysiological characteristics of HPH. Our results showed that Tsantan Sumtang relaxed noradrenaline (NE)-precontracted rat pulmonary artery rings in a concentration-dependent manner in vitro. The PGI2-cAMP (prostaglandin I2-cyclic adenosine monophosphate) pathway, NO-cGMP (nitric oxide-cyclic guanosine monophosphate) pathway, and the opening of K+ channels (inward rectifier K+ channels, large conductance Ca2+-activated K+ channels, and voltage-dependent K+ channels) might play major roles in the vasorelaxation effect. In vivo, the administration of Tsantan Sumtang resulted in a substantial decrease in the rat mean pulmonary artery pressure (mPAP) and the right ventricular hypertrophy index (RVHI). The reduction of thickness of small pulmonary arterial wall and the WT% (the ratio of the vascular wall thickness to the vascular diameter) were observed. The smooth muscle muscularization of the arterials was alleviated by Tsantan Sumtang treatment at the same time. Tsantan Sumtang also reduced remodeling of pulmonary arterioles by suppressing the expression of proliferating cell nuclear antigen (PCNA), α-smooth muscle actin (α-SMA), cyclin D1, and cyclin-dependent kinase 4 (CDK4) through inhibition of p27Kip1 degradation. Therefore, Tsantan Sumtang could be applied as a preventative medication for HPH, which would be a new use for this traditional medicine.

Compound xiebai capsule alleviates pulmonary vascular remodeling in monocrotaline-induced pulmonary arterial hypertension in rats

“…Some studies on the smooth muscle, endothelial cells, organelles, cytoplasm, smooth muscle cells, and connective tissue of the arterial wall have shown that TCM formulations such as tsantan sumtang mitigate PAH-induced ultrastructural changes [19]. The results of the present study agree with those of previous studies on traditional herbal medicines, especially with respect to the CXC-induced amelioration of the deleterious effects of PAH on pulmonary tissues.…”

Oxidative Stress, Kinase Activation, and Inflammatory Pathways Involved in Effects on Smooth Muscle Cells During Pulmonary Artery Hypertension Under Hypobaric Hypoxia Exposure

“…In addition, echinacoside was administered to rats under hypobaric hypoxia (4,500 m), and it reduced pulmonary artery remodeling and pulmonary hypertension ( Gai et al, 2020 ). Administration of another traditional Tibetan medicine, Tsantan Sumtang, prevented pulmonary hypertension in rats exposed to hypobaric hypoxia (4,500 m), reducing pulmonary vascular cell proliferation probably by suppressing cyclin D1 and cyclin-dependent kinase 4 (CDK4) expression through inhibition of p27 kip1 degradation ( He et al, 2018 ).…”

Tsantan Sumtang Restored Right Ventricular Function in Chronic Hypoxia-Induced Pulmonary Hypertension Rats

“…RV function was thought to be the most reliable indicator of prognosis in PAH patients ( Kawakubo et al, 2019 ). Tsantan Sumtang, as one of the medicines of the traditional Tibetan medicine, serves to decrease mPAP and alleviates RV remodeling and fibrosis in HPH rats ( He et al, 2018 ; Dang et al, 2020 ). In this study, we investigated the effect of Tsantan Sumtang on the RV function in HPH rats and studied the underlying mechanism.…”

“…B. L. Burtt and A. W. Hill and Myristica fragrans Houtt, and the wooden heart of Santalum album L. The three herbs are in ratio 1:1:1. We previously showed that the aqueous extract of Tsantan Sumtang alleviated HPH in rats by inhibiting pulmonary vascular cell proliferation and suppressing cyclin D1 and CDK4 expression ( He et al, 2018 ). Tsantan Sumtang also reduces hypoxia-induced RV remodeling and fibrosis by equilibrating ACE-AngII-AT1R and ACE2-Ang1-7-Mas axis of RV tissues of HPH rats ( Dang et al, 2020 ).…”