Tanshinone IIA Prevents Rat Basilar Artery Smooth Muscle Cells Proliferation by Inactivation of PDK1 During the Development of Hypertension

Abstract

Basilar vascular smooth muscle cells (BASMCs) hyperplasia is a prominent feature of cerebrovascular remodeling and stroke during the development of hypertension. Tanshinone IIA (Tan) has been reported to exhibit a protective effect against the pathological features of hypertension. Previous studies have shown that phosphoinostitide-3 kinase (PI3K)/3'-phosphoinostitide dependent kinase (PDK1)/AKT pathway is involved in the regulation of proliferation of various cell types. Therefore, there may be a crosstalk between Tan antihypertension processes and PI3K/PDK1/AKT proliferative effect in BASMCs. To test this hypothesis, we used a 2-kidney, 2-clip hypertension model to examine the effect of Tan on PI3K/PDK1/AKT pathway by cellular, molecular, and biochemical approaches. Our results revealed that the abundance of PDK1 in plasma was paralleled with an increase in blood pressure and the cross-sectional area of basilar artery in hypertensive rats. Tan decreased blood pressure and hypertension-induced PDK1 phosphorylation but produced no effect on the phosphorylation of PI3K. Moreover, Tan attenuated endothelin 1 induced the activation of PDK1/AKT pathway in rat BASMCs. Tan could inhibit cell cycle transition by regulating the expression of cyclin D1 and p27, in turn, prevent proliferation of BASMCs. Our study provides a novel mechanism by which Tan prevents cerebrovascular cell proliferation during hypertension, and thus Tan may be a potential therapeutic agent for cerebrovascular remodeling and stroke.

Tanshinone IIA suppresses gastric cancer cell proliferation and migration by downregulation of FOXM1

“…Recently, the pharmacological properties of tanshinone have attracted great interest. Tanshinone IIA (TNS) is the main component of tanshinone, and a variety of clinical trials and experimental studies have demonstrated the protective effect of TSN on cardiovascular diseases, diabetes and tumors (2,18–21). In GC, Jing et al first reported that TSN induced apoptosis and growth inhibition in vitro and in vivo .…”

Salvia miltiorrhizaBurge (Danshen): a golden herbal medicine in cardiovascular therapeutics

“…In VSMCs, tanshinone IIa inhibits the proliferation and migration of VSMCs by inhibiting the activation of ERK [25] and PDK1 (3-phosphoinositide-dependent protein kinase 1) [66] while activating the BKCa (large-conductance Ca 2+ -activated K + channel) [67] , AMPK (adenosine 5'-monophosphate-activated protein kinase) [68] and Nrf2 [69] pathways. Tanshinone IIa also suppresses the apoptosis of VSMCs [39] , indicating its potential to reduce plaque vulnerability.…”

Atheroprotective Effects and Molecular Targets of Tanshinones Derived From Herbal Medicine Danshen

“…Mechanistically, TSN suppressed the proliferation of SMCs via inhibiting ERK/MAPK, c‐fos, but activating the anti‐oxidative NRF2 pathway . TSN inhibited ET‐1 induced hyperactivation of PDK1 (3‐phosphoinositide‐dependent protein kinase 1)/AKT pathway and altered cell cycle progression (reducing cyclin D1 and increasing p27) in rat basilar vascular SMCs in vitro and decreases blood pressure and hypertension (2‐kidney, 2‐clip model)‐induced PDK1 phosphorylation in vivo . This new mechanism suggests that TSN could be a potential therapeutic drug for treating hypertension‐associated cerebrovascular diseases.…”

“…91 TSN inhibited ET-1 induced hyperactivation of PDK1 (3-phosphoinositide-dependent protein kinase 1)/AKT pathway and altered cell cycle progression (reducing cyclin D1 and increasing p27) in rat basilar vascular SMCs in vitro and decreases blood pressure and hypertension (2-kidney, 2-clip model)-induced PDK1 phosphorylation in vivo. 92 This new mechanism suggests that TSN could be a potential therapeutic drug for treating hypertension-associated cerebrovascular diseases. In line with this evidence, a sulfonate salt derivative of TSN (DS-201) was recently reported to selectively increase the expression and activity of pore-forming α subunit of human large conductance, Ca 2+ -activated K + (BKCa) channel (EC 50 = 66.6 ± 1.5 μM), contributing to TSN-mediated vasorelaxation.…”