Molecular Mechanisms of Cardioprotective Actions of Tanshinones

Table 1

Pharmacological actions of tanshinones in vitro.

Compounds	Cells	Concentrations	Effects	Mechanisms	Reference
Cryptotanshinone	HUVECs	1–9 µM	Antiatherosclerosis action against TNF-α	ET-1, NF-κB ↓; NO/eNOS ↑	[26]
		1–5 µM	Anti-inflammatory actions against H2O2, TNF-α	NF-κB activity ↓; VCAM-1, ICAM-1 ↓	[24]
	HASMCs	2.5–30 µg/mL	Antiatherosclerosis action against TNF-α	MMP-9 ↓; NF-κB, AP-1 ↓; p-ERK1/2, p-p38, p-JNK ↓	[23]
	Rat coronary blood vessels	0.5–50 µM	Vasodilator action	Calcium influx ↓	[25]
	H9c2 cells	3 µM	Antioxidant action against hypoxia	Mitochondrial ↓; Mitochondrial SOD ↑; NO ↓, Ca^2+ ↓	[35]
		0.3–3 µM	Antiapoptotic effects against hypoxia	Bcl-2/Bax ratio ↑; Cytochrome C release ↓; Caspase 3 ↓	[36]
Dihydrotanshinone	Rat coronary artery	IC50 10.4 µM	Vasorelaxation action	Calcium influx ↓	[28]
	Rabbit platelet	IC50 8.7 µM	Antiplatelet action against collagen	Platelet aggregation ↓; Ca^2+ ↓; Arachidonic acid release ↓; Thromboxane B2 ↓	[29]
Tanshinone	VSMCs	0.4–50 µg/mL	Antiproliferation action	p-ERK1/2, cyclin D1 ↓; ↑	[33]
	HUVECs	1–50 µM	Anti-inflammatory actions against TNF-α	GATA-6 ↓; IRF-1 ↓; VCAM-1 ↓	[37]
		7.5–60 µg/mL	Cytoprotection against H2O2	SOD, NO ↑; CD40 ↓	[38]
		1–10 µM		p53, caspase-3 ↓; ATF-3 ↑	[39]
		100 µM	Vasodilator action	NO ↑	[17]
		0.6–60 µM		NO, AMPK/PI3K/Akt ↑	[40]
	Rat coronary arterioles	10–100 µM	Vasodilator action	NO, ↑; Cytochrome P450 ↑	[16]
	HASMCs	0.05–5 µM	Antioxidative actions against TNF-α, AngII, H2O2	GSH, NADPH ↑; Nrf-2 ↑	[41]
	VSMCs	0.1–1 µg/mL	Inhibition of proliferation	p-ERK1/2 ↓; c-fos ↓	[42]
	Neonatal cardiomyocytes	0.1–10 µM	Cytoprotective effects against H2O2	DNA fragmentation ↓	[19]
		0.1–3 µM	Antiapoptotic/antioxidant effects against doxorubicin	ROS ↓; Bcl-xl ↑, caspase 3 ↓; p-Akt ↑	[21]
		0.5–2 µM		H2O2, ↓; Bcl-2/Bax ratio ↑	[43]
		100 µM	Antioxidant action against H2O2	Ca^2+ ↓MMP ↑	[44]
		2–8 µM	Anti-inflammatory effects against TNF-α	MCP-1 ↓; TGF-β1 secretion ↓	[18]
		10 µM	Antiapoptosis action against hypoxia	miR-133 ↑; p-ERK1/2 ↑	[45]
		10 µM	Cytoprotective effects against hypoxia	p-p38MAPK ↓; SRF, MEF2 ↓; Cx43 ↑	[46]
		10–100 µM	Antihypertrophic action against isoproterenol, AngII	Ca^2+ ↓; Calcineurin, NFATc3 ↓; ANP, BNP, β-MHC ↓	[47]
		10^−8 g/L		Cell size ↓; Protein synthesis rate ↓; c-fos, c-jun ↓	[48]
		0.1–10 µM	Antiapoptotic action against AngII	p-Akt, Bcl-xl ↑; Cytochrome c, caspase 3 ↓	[49]
Tanshinone IIA	Neonatal cardiac fibroblasts	10–100 µM	Antifibrosis action against TGF-β	p-Smad3, CTGF, COLI ↓; Smad7 ↑	[50]
		0.1–10 µM	Antiproliferation against AngII	ET-1 expression ↓; p-ERK1/2 ↓; NO, p-eNOS ↑	[51]
		3–30 µM	Antifibrosis action against AngII	Collagen type 1 ↓; MMP-1 ↓; ROS ↓; NADPH activity ↓; P47 ↓	[52]
	Rat cardiac fibroblasts	0.1–10 µM	Antifibrosis action against H2O2	Collagen synthesis ↓; NADPH oxidase ↓; ↓	[53]
	Human cardiac fibroblasts	0.1–10 µM	Inhibition of AngII-induced extracellular matrix remodeling	TGF-β1 ↓, pSmad 2 ↓, p-P38 ↓, MMP9 ↓, p-ERK ↓, p-IkB ↓, p65 ↓, interfering Smad-mediated recruitment of CBP1 via the activation of CREB	[54]
	H9c2 cells	0.3–3 µM	Antiapoptotic effects against hypoxia	Bcl-2/Bax ratio ↑; Cytochrome C release ↓; Caspase 3 ↓; HIF-1α ↓	[36]
		3 µM	Antioxidant action against hypoxia	Mitochondrial ↓; Mitochondrial SOD ↑; NO, Ca^2+ ↓; ATP level ↑	[35]
		1–10 µM	Protection against injury induced by oxygen-glucose deprivation/recovery	Apoptosis ↓, TNF-α ↓, caspase-3 ↓, Bax/Bcl-2 ↓; NF-κB ↓, p-JNK ↓; PI3k	[55]
Tanshinone; VI	Neonatal cardiomyocytes/cardiac fibroblast	0.1–10 µM	Antihypertrophic action against AngII, IGF-1, and ET-1	p-ERK1/2 ↓; Natriuretic peptide ↓	[56]

AngII, angiotensin II; ANP, arterial natriuretic peptide; ATF-3, activating transcription factor-3; , high conductance Ca²⁺ activated K⁺ channels; β-MHC, β-myosin heavy chain; BNP, brain natriuretic peptide; CD40, cluster of differentiation 40; Cx43, connexin 43; [Ca²⁺], intracellular calcium; ET-1, endothelin-1; ERK, extracellular signal-regulated kinase; G6PDH, glucose 6-phosphate dehydrogenase; GSH, glutathione; GPx, glutathione peroxidase; ICAM-1, intracellular adhesion molecule-1; IGF-1, insulin-like growth factor-1; I/R, ischemia reperfusion; IRF-1, interferon regulatory factor-1; MEF2, myocyte enhancer factor 2; MMP, mitochondrial membrane potential; MMP-9, matrix metalloproteinases-9; NFATc3, nuclear factor of activated T-cells cytoplasmic 3; NF-κB, nuclear factor-κB; Nrf2, nuclear factor-E2-related factor; NO, nitric oxide; HUVECs, human umbilical vein endothelial cells; HASMCs, human aortic smooth muscle cells; p38MAPK, p38 mitogen-activated protein kinase; ROS, reactive oxygen species; SOD, superoxide dismutase; SRF, serum reaction factor; VCAM-1, vascular cell adhesion molecule-1; VSMCs, vascular smooth muscle cells.