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.
Highlights
Pulmonary hypertension (PH) is a group of clinical disorders that feature an abnormal elevation in the pulmonary circulatory pressure and are characterized by a sustained increase in pulmonary vascular resistance and vascular remodeling, which leads to right ventricular failure and death [1, 2].Hypoxia-induced pulmonary hypertension (HPH) is a type of PH that occurs among residents and travelers at high altitude
After the different inhibitors were added, we found that the vasorelaxation caused by the Tsantan Sumtang treatment of small pulmonary artery rings that had been contracted with 1 μmol/L NE was significantly blocked by L-NAME, IMT, TEA, BaCl2, and 4-AP with maximum contractions of 63.23±0.37%, 35.90±0.64%, 64.50±0.38%, 24.56±0.38%, and 40.87±0.40%, respectively, (P
It is well known that chronic hypoxia causes pulmonary vasoconstriction and pulmonary vascular cells proliferation, progressive right ventricular hypertrophy, and eventual right heart failure, and the major pathological changes of HPH are the pulmonary vasoconstriction and remodeling resulting from pulmonary artery smooth muscle cell (PASMC) proliferation [19,20,21,22,23]
Summary
Pulmonary hypertension (PH) is a group of clinical disorders that feature an abnormal elevation in the pulmonary circulatory pressure and are characterized by a sustained increase in pulmonary vascular resistance and vascular remodeling, which leads to right ventricular failure and death [1, 2].HPH is a type of PH that occurs among residents and travelers at high altitude. Pulmonary hypertension (PH) is a group of clinical disorders that feature an abnormal elevation in the pulmonary circulatory pressure and are characterized by a sustained increase in pulmonary vascular resistance and vascular remodeling, which leads to right ventricular failure and death [1, 2]. It has been reported that people living on a plateau may suffer from minor to moderate pulmonary vasoconstriction and hypertension, and those with a maladaptation to hypoxia may induce hypoxia-related diseases, among which HPH appears in approximately 5–10% of cases [3,4,5]. BioMed Research International in right ventricular hypertrophy and heart failure. As the key pathophysiological changes with HPH, vasoconstriction and vascular remodeling of the pulmonary artery impact the long-term prognosis of the patient, especially regarding myocardial damage, right ventricular hypertrophy, heart failure, and brain function decline [1, 2]
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