Sodium tanshinone IIA sulfonate inhibits canonical transient receptor potential expression in pulmonary arterial smooth muscle from pulmonary hypertensive rats.
Danshen, the dried root of Salvia miltiorrhiza, is widely used in clinics in China for treating various diseases, including cardiovascular diseases. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA isolated as the major active component from Danshen, was recently reported to be effective in attenuating the characteristic pulmonary vascular changes associated with chronically hypoxic pulmonary hypertension (CHPH); however, the underlying detailed mechanisms are poorly understood. In this study, we investigated the effects of STS on basal intracellular Ca(2+) concentration ([Ca(2+)](i)) and store-operated Ca(2+) entry (SOCE) in distal pulmonary arterial smooth muscle cells (PASMCs) exposed to prolonged hypoxia or isolated from CHPH rats. SOCE measured by Mn(2+) quenching of Fura-2 fluorescence in PASMCs from rats exposed to chronic hypoxia (10% O(2), 21 d) was increased by 59%, and basal [Ca(2+)](i) was increased by 119%; this effect was inhibited by intraperitoneal injection of STS. These inhibitory effects of STS on hypoxic increases of SOCE and basal [Ca(2+)](i) were associated with reduced expression of canonical transient receptor potential (TRPC)1 and TRPC6 in distal pulmonary arterial smooth muscle and decreases on right ventricular pressure, right ventricular hypertrophy, and peripheral pulmonary vessel thickening. In ex vivo cultured distal PASMCs from normoxic rats, STS (0-25 μM) dose-dependently inhibited hypoxia-induced cell proliferation and migration, paralleled with attenuation in increases of basal [Ca(2+)](i), SOCE, mRNA, and protein expression of TRPC1 and TRPC6. STS also relieved right ventricular systolic pressure, right ventricular hypertrophy, and TRPC1 and TRPC6 protein expression in distal pulmonary arteries in a monocrotaline-induced rat model of pulmonary arterial hypertension. These results indicate that STS prevents pulmonary arterial hypertension development likely by inhibiting TRPC1 and TRPC6 expression, resulting in normalized basal [Ca(2+)](i) and attenuated proliferation and migration of PASMCs.
Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China. wlu92@yahoo.com
Jian
J
Wang
Qian
Q
Jiang
Limei
L
Wan
Kai
K
Yang
Yi
Y
Zhang
Yuqin
Y
Chen
Elizabeth
E
Wang
Ning
N
Lai
Lei
L
Zhao
Hua
H
Jiang
Yueqian
Y
Sun
Nanshan
N
Zhong
Pixin
P
Ran
Wenju
W
Lu
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D010616:Phenanthrenes / Q000494:pharmacology*; D008517:Phytotherapy; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D027561:Salvia miltiorrhiza; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D015220:Calcium Channels; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C492145:Trpc6 protein, rat; C096351:transient receptor potential cation channel, subfamily C, member 1; C024894:tanshinone II A sodium sulfonate; D002118:Calcium