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Tsantan Sumtang attenuated chronic hypoxia-induced right ventricular structure remodeling and fibrosis by equilibrating local ACE-AngII-AT1R/ACE2-Ang1-7-Mas axis in rat.
J Ethnopharmacol. 2020 Mar 25; 250:112470.JE

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Tsantan Sumtang, which consists of Choerospondias axillaris (Roxb.) Burtt et Hill, Myristica fragrans Houtt and Santalum album L, is a traditional and common prescription of Tibetan medicine. Tsantan Sumtang originates from Four Tantra with properties of nourishing heart and has been used as a folk medicine for cardiovascular diseases and heart failure in Qinghai, Tibet and Inner Mongolia. Our previous studies found that Tsantan Sumtang showed beneficial effects on right ventricular structure in hypoxia rats, while the underling mechanism remains unclear.

AIM OF THE STUDY

To elucidate the underlying mechanisms of Tsantan Sumtang attenuated right ventricular (RV) remodeling and fibrosis of chronic hypoxia-induced pulmonary arterial hypertension (HPAH) rats.

MATERIALS AND METHODS

Fifty male Sprague Dawley (SD) rats (170 ± 20 g) were randomly divided into control group, hypoxia group, and hypoxia + Tsantan Sumtang groups (1.0 g· kg-1·day-1, 1.25 g· kg-1·day-1, 1.5 g ·kg-1·day-1). Rats in the hypoxia group and hypoxia + Tsantan Sumtang groups were maintained in a hypobaric chamber by adjusting the inner pressure and oxygen content to simulate an altitude of 4500 m for 28 days. The mean pulmonary arterial pressure (mPAP), right ventricle hypertrophy index (RVHI), the ratio of RV weight to tibia length (TL) (RV/TL), heart rate (HR) and RV systolic pressure (RVSP) was determined. Histomorphological assay of RV structure was evaluated by hematoxylin and eosin (HE) staining. RV tissue fibrosis was assessed by collagen proportion area (CPA), collagen I, collagen III and hydroxyproline content. CPA was obtained by picro-sirius red staining (PSR). The expression of collagen I and collagen III were detected by immunohistochemistry and western blotting. The hydroxyproline content was detected by alkaline hydrolysis. In addition, the level of angiotensin II (AngII) and angiotensin 1-7 (Ang1-7) in RV tissue was tested by enzyme-linked immune sorbent assay (ELISA). Protein expression of angiotensin-converting enzyme (ACE), AngII, AngII type 1 receptor (AT1R), angiotensin-converting enzyme 2 (ACE2), Mas receptor (Mas) were determined by immunohistochemistry and western blotting. mRNA level of ACE, AT1R, ACE2, Mas were tested by qPCR. The chemical profile of Tsantan Sumtang was revealed by UHPLC-Q-Exactive hybrid quadrupole-orbitrap mass analysis.

RESULTS

Our results showed that RVHI, RV/TL and RVSP were significantly increased in HPAH rat. Furthermore, levels of collagen I, collagen III and hydroxyproline were up-regulated in RV tissue under hypoxia. We found that RV hypertrophy and fibrosis were associated with increased expression of ACE, AngII, AT1R as well as decreased expression of ACE2, Ang1-7 and Mas. RV remodeling and fibrosis were attenuated after Tsantan Sumtang administration by up-regulating ACE2 and Mas level as well as down-regulating ACE, AngII and AT1R levels in RV tissue. 35 constituents in Tsantan Sumtang were identified.

CONCLUSION

Tsantan Sumtang attenuated RV remodeling and fibrosis in rat exposed to chronic hypoxia. The pharmacological effect of Tsantan Sumtang was based on equilibrating ACE-AngII-AT1R and ACE2-Ang1-7-Mas axis of RV tissue in HPAH rat.

Authors+Show Affiliations

Research Center for High Altitude Medicine, Qinghai University, Xining, 810001, China; Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Xining, 810001, China; Medical College, Qinghai University, Xining, 810001, China.Technical Center of Xining Customs District, Key Laboratory of Food Safety Research in Qinghai Province, Xining, 810003, China.Research Center for High Altitude Medicine, Qinghai University, Xining, 810001, China; Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Xining, 810001, China.Medical College, Qinghai University, Xining, 810001, China.Research Center for High Altitude Medicine, Qinghai University, Xining, 810001, China; Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Xining, 810001, China.Research Center for High Altitude Medicine, Qinghai University, Xining, 810001, China; Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Xining, 810001, China. Electronic address: zhanqiang_li@163.com.Research Center for High Altitude Medicine, Qinghai University, Xining, 810001, China; Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Xining, 810001, China. Electronic address: ludianxiang@qhu.edu.cn.Research Center for High Altitude Medicine, Qinghai University, Xining, 810001, China; Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Xining, 810001, China. Electronic address: geriligao@hotmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31862407

Citation

Dang, Zhancui, et al. "Tsantan Sumtang Attenuated Chronic Hypoxia-induced Right Ventricular Structure Remodeling and Fibrosis By Equilibrating Local ACE-AngII-AT1R/ACE2-Ang1-7-Mas Axis in Rat." Journal of Ethnopharmacology, vol. 250, 2020, p. 112470.
Dang Z, Su S, Jin G, et al. Tsantan Sumtang attenuated chronic hypoxia-induced right ventricular structure remodeling and fibrosis by equilibrating local ACE-AngII-AT1R/ACE2-Ang1-7-Mas axis in rat. J Ethnopharmacol. 2020;250:112470.
Dang, Z., Su, S., Jin, G., Nan, X., Ma, L., Li, Z., Lu, D., & Ge, R. (2020). Tsantan Sumtang attenuated chronic hypoxia-induced right ventricular structure remodeling and fibrosis by equilibrating local ACE-AngII-AT1R/ACE2-Ang1-7-Mas axis in rat. Journal of Ethnopharmacology, 250, 112470. https://doi.org/10.1016/j.jep.2019.112470
Dang Z, et al. Tsantan Sumtang Attenuated Chronic Hypoxia-induced Right Ventricular Structure Remodeling and Fibrosis By Equilibrating Local ACE-AngII-AT1R/ACE2-Ang1-7-Mas Axis in Rat. J Ethnopharmacol. 2020 Mar 25;250:112470. PubMed PMID: 31862407.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tsantan Sumtang attenuated chronic hypoxia-induced right ventricular structure remodeling and fibrosis by equilibrating local ACE-AngII-AT1R/ACE2-Ang1-7-Mas axis in rat. AU - Dang,Zhancui, AU - Su,Shanshan, AU - Jin,Guoen, AU - Nan,Xingmei, AU - Ma,Lan, AU - Li,Zhanqiang, AU - Lu,Dianxiang, AU - Ge,Rili, Y1 - 2019/12/17/ PY - 2019/04/11/received PY - 2019/12/02/revised PY - 2019/12/09/accepted PY - 2019/12/22/pubmed PY - 2020/11/5/medline PY - 2019/12/22/entrez KW - ACE-AngII-AT1R KW - ACE2-Ang1-7-Mas KW - Chronic hypoxia induced pulmonary arterial hypertension KW - Right ventricular remodeling and fibrosis KW - Tsantan Sumtang KW - dehydrodiisoeugenol (PubChem CID: 377545026) KW - ellagic acid (PubChem CID: 136367393) KW - gallic acid (PubChem CID: 348273087) KW - germacrone (PubChem CID: 377577656) KW - guaiacin (PubChem CID: 336269518) KW - isoquercitrin (PubChem CID: 377477425) KW - myricetin (PubChem CID: 377309462) KW - myristic acid (PubChem CID: 376241985) KW - myristicin (PubChem CID: 348290984) KW - quercetin (PubChem CID: 377309355) KW - quercitrin (PubChem CID: 254778366) KW - ursolic acid (PubChem CID: 348275801) SP - 112470 EP - 112470 JF - Journal of ethnopharmacology JO - J Ethnopharmacol VL - 250 N2 - ETHNOPHARMACOLOGICAL RELEVANCE: Tsantan Sumtang, which consists of Choerospondias axillaris (Roxb.) Burtt et Hill, Myristica fragrans Houtt and Santalum album L, is a traditional and common prescription of Tibetan medicine. Tsantan Sumtang originates from Four Tantra with properties of nourishing heart and has been used as a folk medicine for cardiovascular diseases and heart failure in Qinghai, Tibet and Inner Mongolia. Our previous studies found that Tsantan Sumtang showed beneficial effects on right ventricular structure in hypoxia rats, while the underling mechanism remains unclear. AIM OF THE STUDY: To elucidate the underlying mechanisms of Tsantan Sumtang attenuated right ventricular (RV) remodeling and fibrosis of chronic hypoxia-induced pulmonary arterial hypertension (HPAH) rats. MATERIALS AND METHODS: Fifty male Sprague Dawley (SD) rats (170 ± 20 g) were randomly divided into control group, hypoxia group, and hypoxia + Tsantan Sumtang groups (1.0 g· kg-1·day-1, 1.25 g· kg-1·day-1, 1.5 g ·kg-1·day-1). Rats in the hypoxia group and hypoxia + Tsantan Sumtang groups were maintained in a hypobaric chamber by adjusting the inner pressure and oxygen content to simulate an altitude of 4500 m for 28 days. The mean pulmonary arterial pressure (mPAP), right ventricle hypertrophy index (RVHI), the ratio of RV weight to tibia length (TL) (RV/TL), heart rate (HR) and RV systolic pressure (RVSP) was determined. Histomorphological assay of RV structure was evaluated by hematoxylin and eosin (HE) staining. RV tissue fibrosis was assessed by collagen proportion area (CPA), collagen I, collagen III and hydroxyproline content. CPA was obtained by picro-sirius red staining (PSR). The expression of collagen I and collagen III were detected by immunohistochemistry and western blotting. The hydroxyproline content was detected by alkaline hydrolysis. In addition, the level of angiotensin II (AngII) and angiotensin 1-7 (Ang1-7) in RV tissue was tested by enzyme-linked immune sorbent assay (ELISA). Protein expression of angiotensin-converting enzyme (ACE), AngII, AngII type 1 receptor (AT1R), angiotensin-converting enzyme 2 (ACE2), Mas receptor (Mas) were determined by immunohistochemistry and western blotting. mRNA level of ACE, AT1R, ACE2, Mas were tested by qPCR. The chemical profile of Tsantan Sumtang was revealed by UHPLC-Q-Exactive hybrid quadrupole-orbitrap mass analysis. RESULTS: Our results showed that RVHI, RV/TL and RVSP were significantly increased in HPAH rat. Furthermore, levels of collagen I, collagen III and hydroxyproline were up-regulated in RV tissue under hypoxia. We found that RV hypertrophy and fibrosis were associated with increased expression of ACE, AngII, AT1R as well as decreased expression of ACE2, Ang1-7 and Mas. RV remodeling and fibrosis were attenuated after Tsantan Sumtang administration by up-regulating ACE2 and Mas level as well as down-regulating ACE, AngII and AT1R levels in RV tissue. 35 constituents in Tsantan Sumtang were identified. CONCLUSION: Tsantan Sumtang attenuated RV remodeling and fibrosis in rat exposed to chronic hypoxia. The pharmacological effect of Tsantan Sumtang was based on equilibrating ACE-AngII-AT1R and ACE2-Ang1-7-Mas axis of RV tissue in HPAH rat. SN - 1872-7573 UR - https://www.unboundmedicine.com/medline/citation/31862407/Tsantan_Sumtang_attenuated_chronic_hypoxia_induced_right_ventricular_structure_remodeling_and_fibrosis_by_equilibrating_local_ACE_AngII_AT1R/ACE2_Ang1_7_Mas_axis_in_rat_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-8741(19)31387-X DB - PRIME DP - Unbound Medicine ER -