Active Ingredients of Salviae Miltiorrhizae and Their Current Research Status in Cardiovascular Diseases

Salviae Miltiorrhizae, the dried roots and rhizomes of the Salvia genus in the Labiatae family, is a commonly used traditional Chinese medicine for promoting blood circulation and removing blood stasis. It possesses various effects including activating blood circulation to dissipate blood stasis, relieving pain through dredging the meridians, calming the heart and eliminating vexation, cooling the blood, and resolving abscesses. Its actions on the blood and cardiovascular system are particularly remarkable, with clinically proven effects in improving microcirculation, anticoagulation, antithrombotic activity, and blood pressure reduction, indicating broad prospects for development.

Salviae Miltiorrhizae contains a diverse range of chemical components, which can be broadly classified into two major categories: diterpenoid liposoluble compounds dominated by tanshinones, such as tanshinone I-VI, tanshinone B, cryptotanshinone, dihydrotanshinone I, and isotanshinone IIA; and phenolic acid-based water-soluble components, including danshensu, salvianolic acid A, salvianolic acid B, protocatechuic aldehyde, and rosmarinic acid. In addition, it also contains nitrogen-containing compounds, lactones, as well as polysaccharides, flavonoids, sterols, triterpenes, and other components.

As a crucial medicine for promoting blood circulation and removing blood stasis, Salviae Miltiorrhizae has been used in the treatment of cardiovascular diseases in China for over two thousand years. The active ingredients of Salviae Miltiorrhizae and its preparations exhibit certain cardiovascular protective effects, including anti-atherosclerosis, improvement of myocardial remodeling, anti-myocardial ischemia, and anti-arrhythmia. Preparations with Salviae Miltiorrhizae as the main ingredient, such as Compound Danshen Tablet, Compound Danshen Dropping Pills, and Guanxin Danshen Capsule, have been widely used in the treatment of cardiovascular diseases like ischemic heart disease, hypertension, and hyperlipidemia.

1. Anti-Atherosclerosis Effect

The oxidative modification of low-density lipoprotein (LDL) is a significant contributor to the development of atherosclerosis (AS). Studies have demonstrated that salvianolic acid A, a water-soluble component of Salviae Miltiorrhizae, can effectively inhibit Cu2+-induced oxidation of human serum LDL. Additionally, salvianolate, a polyphenolic salt derived from Salviae Miltiorrhizae, mitigates AS induced by a high-fat diet combined with vitamin D3 injection by suppressing inflammatory processes, such as modulating regulatory T cells (Tregs) and cytokine levels. Furthermore, research into the mechanism of action of salvianolic acid A on AS, both in vitro and in vivo, indicates that its protective effects in AS are closely related to inhibiting oxidative stress and inflammation, as well as improving endothelial dysfunction.

Tanshinone IIA inhibits the progression of AS through multiple mechanisms, including correcting endothelial dysfunction, inhibiting the proliferation and migration of smooth muscle cells, suppressing inflammation, reducing foam cell formation, inhibiting platelet aggregation, and promoting the inflammatory resolution of neutrophils. Cryptotanshinone significantly attenuates AS plaque formation and enhances plaque stability in ApoE knockout (ApoE -/-) mice by inhibiting the expression of lectin-like oxidized LDL receptor-1 (LOX-1) and matrix metalloproteinase-9 (MMP-9), as well as inhibiting reactive oxygen species generation and activating NF-κB. Salvianolic acid B, on the other hand, exerts its anti-AS effects by activating nuclear factor erythroid 2-related factor 2 (Nrf2), increasing the expression of heme oxygenase-1 (HO-1), and thereby inhibiting the proliferation, migration, and inflammation of vascular cells.

Hyperlipidemia is a risk factor for AS and related cardiovascular diseases. Animal experimental studies have shown that Danhong Injection, a preparation containing Salviae Miltiorrhizae extract, exhibits significant blood lipid-regulating effects and is widely used in the treatment of cardiovascular diseases. By establishing a hyperlipidemia mouse model through a high-fat diet, the mechanism of blood lipid regulation by methanol extracts of Salviae Miltiorrhizae was studied. It was found that the methanol extract of Salviae Miltiorrhizae primarily improves hyperlipidemia in mice fed a high-fat diet by inhibiting the elevation of serum triglyceride levels.

Furthermore, in vivo experiments evaluating the regulation of hepatic lipid metabolism and potential molecular mechanisms of tanshinone IIA in hyperlipidemic rats revealed that tanshinone IIA can reduce lipid deposition in the liver of hyperlipidemic rats. It also modulates the expression of proteins in the microRNA-33a and sterol regulatory element-binding protein-2/Proprotein Convertase Subtilisin/Kexin Type 9 (SREBP-2/PCSK9) signaling pathway.

2.Anti-Myocardial Fibrosis Effect

Angiotensin II (Ang II) is a crucial factor in the development of myocardial fibrosis. Studies have found that tanshinone IIA can attenuate Ang II-induced increases in collagen I expression and synthesis in cardiac fibroblasts by inhibiting intracellular reactive oxygen species generation, reducing NADPH oxidase activity, and downregulating the expression of its subunit p47. TGF-β and microRNA (miR-) 29b play significant roles in myocardial fibrosis and the functional regulation of cardiac fibroblasts. Research indicates that medium to high doses of tanshinone IIA can inhibit post-infarction myocardial fibrosis and improve left ventricular dysfunction in rats with acute myocardial infarction by upregulating miR-29b expression mediated by the TGF-β-Smad3 signaling pathway.

Pretreatment of cardiac fibroblasts with tanshinone IV can attenuate IGF-1-induced myocardial fibrosis by diminishing IGF-1-induced phosphorylation of extracellular signal-regulated kinase (pERK) and protein kinase B (pAkt). Additionally, salvianolic acid A inhibits the migration of neonatal rat cardiac fibroblasts, blocks fibroblast transdifferentiation, and suppresses the secretion of intercellular adhesion molecule (ICAM), IL-6, soluble vascular cell adhesion molecule-1 (sVCAM-1), as well as collagen secretion induced by MMP-9CD. This suggests that salvianolic acid A acts as a novel MMP-9 inhibitor with potential cardioprotective effects, inhibiting hypertensive myocardial fibrosis.

3.Inhibition of Myocardial Hypertrophy

Myocardial hypertrophy serves as a risk factor for myocardial ischemia, arrhythmia, and sudden cardiac death. Research has demonstrated that tanshinone IIA can inhibit the development of left ventricular hypertrophy by upregulating Bcl-2 expression and downregulating the expression of Bax and p53. Studies on spontaneously hypertensive rats (SHR) investigating the protective effects of tanshinone IIA against myocardial hypertrophy found that it inhibits the Cys-C/Wnt pathway, reducing related proteins in the Cys-C/Wnt signaling pathway and exerting cardioprotective effects.

Salvianolic acid B, when acting on angiotensin II (Ang II)-induced neonatal rat cardiomyocytes hypertrophy, reduces the expression of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) mRNA, as well as decreases cell surface area, indicating that salvianolic acid B is an effective PARP-1 inhibitor that protects cardiomyocytes from Ang II-induced hypertrophy by inhibiting PARP-1. Using a type 2 diabetes mellitus (T2DM) mouse model established by a high-fat diet combined with intraperitoneal injection of streptozotocin, the effects of salvianolic acid B on myocardial hypertrophy in this model were studied. Results showed that salvianolic acid B significantly reduced the cross-sectional area of myocardial cells, decreased the heart weight/tibial length ratio, upregulated the level of peroxisome proliferator-activated receptor-α (PPARα), and improved myocardial hypertrophy in T2DM mice.

Furthermore, research on the effects of danshensu in an isoproterenol-induced myocardial hypertrophy rat model revealed that danshensu significantly reduced the heart weight index and left ventricular weight index, decreased serum malondialdehyde (MDA) content in a dose-dependent manner, and increased superoxide dismutase (SOD) content. Danshensu's antioxidant effects and reversal of downregulated connexin 43 (CX43) effectively improved cardiac function and provided myocardial protection in the myocardial hypertrophy rat model.

4.Anti-Myocardial Ischemia Effects

Cellular experiments on myocardial protection have demonstrated that tanshinone IIA-dominated extracts from Salviae Miltiorrhizae possess estrogen-like effects. These extracts can activate protein kinase B (Akt) through estrogen receptor mediation and inhibit Leu27IGF-II-induced apoptosis in cardiomyocytes by blocking insulin-like growth factor II (IGF-II) receptor signaling activation. This suggests that these extracts may serve as potential selective estrogen receptor modulators (SERMs) for preventing cardiomyocyte apoptosis and treating cardiovascular diseases without increasing the risk of breast cancer.

Furthermore, animal studies have found that salvianolic acid A exerts anti-apoptotic effects during myocardial ischemia-reperfusion (I/R) injury by activating extracellular signal-regulated kinase 1/2 (ERK1/2) and inhibiting c-Jun N-terminal kinase (JNK).

In vitro and in vivo studies have shown that tanshinone IIA can significantly reduce the percentage of myocardial infarction area to the area at risk (AN/AAR ratio), decrease serum levels of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), mitochondrial malondialdehyde (MDA), and hydrogen peroxide (H2O2), while enhancing the activities of superoxide dismutase (SOD) and succinate dehydrogenase (SDH). It achieves this by activating the PI3K/AKT pathway, which in turn activates the mTOR pathway, thereby alleviating myocardial ischemia-reperfusion injury (MIRI). Research investigating whether administering tanshinone IIA before prolonged reperfusion following sustained ischemia can effectively mitigate MIRI found that intravenous injection of tanshinone IIA before reperfusion reduced the myocardial infarction area in rats, decreased levels of phosphorylated Akt and endothelial nitric oxide synthase (eNOS), and attenuated mitochondrial permeability transition (MPT). This protective effect could be abolished by the PI3K inhibitor LY294002, indicating that tanshinone IIA protects the myocardium from MIRI via the PI3K/Akt pathway.

Salvianolic acid B can reverse the upregulation of miR-30a expression in MIRI cardiomyocytes and alleviate MIRI-induced myocardial autophagy through the PI3K/AKT pathway. An acute myocardial ischemia rat model was established using isoproterenol, which increased glycolysis and caused significant myocardial damage. After intervention with Compound Danshen Dropping Pills, the primary energy production mode in cardiac tissue shifted towards fatty acid metabolism, thereby increasing energy production and alleviating myocardial ischemia. Additionally, Compound Danshen Dropping Pills protect cardiomyocytes from MIRI by regulating myocardial enzymes, reducing infarction area, and enhancing free radical scavenging capacity. They also inhibit rat cardiomyocyte apoptosis by activating the AKT-eNOS signaling pathway.

As representative compounds in Salviae Miltiorrhizae, tanshinones possess various pharmacological effects such as protecting vascular endothelium, improving microcirculation, anti-inflammatory, and anti-infective properties. They are clinically used in the treatment of cardiovascular and cerebrovascular diseases, cancer, diabetes, liver diseases, and so on. In recent years, more research at home and abroad has focused on the pharmacological effects and mechanisms of action of tanshinones. However, due to the diversity of tanshinone compounds, the targets and mechanisms of action of each component are not identical, and further exploration and verification are still required. Amidst the trend of "returning to nature" in health concepts, Salviae Miltiorrhizae, as a typical natural medicinal material, holds vast potential for development.

Reference Materials:

[1] Wang Jing, Dong Zhenhua, Lu Bo, Fu Deyu. Research Progress on the Active Ingredients and Preparations of Salviae Miltiorrhizae in Cardiovascular Diseases [J]. Lishizhen Medicine and Materia Medica Research, 2019, 30(06): 1453-1456.

[2] Sun Ningyuan, Zhu Xuelin, Chen Jun. Research Progress on the Anti-fibrotic Pharmacological Effects and Mechanisms of Chemical Constituents in Salviae Miltiorrhizae [J]. Chinese Journal of Experimental Traditional Medical Formulae, 2020, 26(22): 201-208.

About the Author

Xiaonisha, a food technology professional, graduated from the School of Food Science and Engineering, South China University of Technology, with a Master's degree in Food Science. Currently, she is employed at a large domestic drug research and development company, engaged in the development and research of nutritional foods.