Research Progress on the Pharmacological Effects of Salvianolic Acid B in Cardiovascular Diseases

Sal B is a water-soluble component extracted from Danshen (Salvia miltiorrhiza). It is a phenolic acid compound formed by the condensation of 3 molecules of danshensu and 1 molecule of caffeic acid. The chemical structure of Sal B contains 9 phenolic hydroxyl groups, which can provide active hydrogen to prevent lipid peroxidation. (Please note that the figure of its structure is not provided in the text, but conceptually we understand its complex structure.)

Research has shown that Sal B exhibits strong antioxidant and free radical scavenging effects in various free radical generation systems. Sal B possesses various pharmacological activities and can protect blood vessels through multiple pathways and targets. Therefore, it has extensive applications in the treatment of cardiovascular diseases.

1. Antioxidant Properties

Research indicates that Sal B is capable of eliminating oxygen free radicals and inhibiting lipid peroxidation, making it one of the natural products with strong antioxidant effects. Studies have found that Sal B can improve histopathological damage in rats, prevent leakage of serum creatine kinase (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH), and significantly increase the activity of rat catalase (CAT), glutathione peroxidase (GSH-Px), and reduced glutathione (GSH). In vitro experiments show that Sal B can reduce the activity of LDH in the culture supernatant and the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in cardiomyocytes, providing a certain protective effect against cardiomyocyte apoptosis and enhancing its antioxidant properties. By establishing a sepsis model in rats, detecting troponin T, creatine kinase isoenzyme, and interleukin-6 (IL-6) levels using enzyme-linked immunosorbent assay, measuring the activity of superoxide dismutase and MDA content through colorimetry, observing histopathological changes in myocardial tissue, and detecting the expression levels of apoptosis-related proteins such as caspase-3, B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X protein (Bax), it was found that Sal B inhibits the release of oxygen free radicals in rats by affecting autophagy proteins, thereby enhancing the ability to resist oxidative stress.

2.Anti-Apoptotic Effects

Studies have found that Sal B can induce apoptosis of cardiovascular endothelial cells, preventing the thickening of the cardiovascular endothelium. After administering Sal B to rats with acute myocardial infarction (AMI), it was discovered that Sal B can inhibit the poly(ADP-ribose) polymerase-1 (PARP-1) pathway, improve the integrity of mitochondria and nuclei in rat myocardial tissue, and inhibit cardiomyocyte apoptosis. Through the establishment of a diabetes mellitus (DM) model, it was found that Sal B may resist oxidative stress injury and apoptosis of cardiomyocytes induced by high-glucose culture by activating the expression of nicotinamide adenine dinucleotide-dependent enzyme (SIRT1).

3.Protective Effects Against Myocardial Infarction

Using coronary artery ligation to construct a rat model of myocardial infarction (MI), the protective effects of Sal B on MI were investigated. The results showed that compared with the control group, Sal B exhibited significant cardiac protective effects against MI. Mechanism studies have revealed that Sal B primarily exerts its protective effects on the heart by inhibiting the upregulation of leptin and endothelin-reactive oxygen species (ET-ROS) as well as restoring the normal expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and phospholamban in cardiomyocytes of the myocardium.

4.Inhibitory Effects on Cardiomyocyte Hypertrophy

In studying the effects of Sal B on angiotensin II (Ang II)-induced cardiomyocyte hypertrophy in neonatal rats, the results showed that Sal B was able to inhibit Ang II-induced cardiomyocyte hypertrophy. Simultaneously, it was found that the expression of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) mRNA decreased, and the cell surface area reduced. Mechanism studies revealed that Sal B inhibits the activity of poly(ADP-ribose) polymerase-1 (PARP-1), and overexpression of PARP-1 attenuates the anti-cardiomyocyte hypertrophy effect of Sal B. These studies indicate that Sal B has a good inhibitory effect on cardiomyocyte hypertrophy.

5.Protective Effects Against Ischemia/Reperfusion (MI/R) Injury

In a rat model of myocardial ischemia-reperfusion injury, Sal B has been shown to reduce post-injury serum CPK levels and decrease the infarct size. Furthermore, Sal B significantly inhibits the activation of the renin-angiotensin-aldosterone system, regulates the levels of PGI2 and TXA2, and reduces the release of inflammatory cytokines. These results confirm the protective effects of Sal B on ischemia-reperfusion cardiomyocytes from the perspective of inhibiting inflammation. Similar effects have also been observed in hypoxic-reoxygenation models of isolated hearts and cultured cardiomyocytes.

Research suggests that the combined application of Sal B and 5-azacytidine can induce the differentiation of rat bone marrow mesenchymal stem cells into cardiomyocyte-like cells. The potential mechanism is that Sal B promotes the secretion of certain cytokines from bone marrow mesenchymal cells, thereby influencing the expression of genes such as NKX2.5 and GATA-4 that are favorable for the formation of cardiomyocyte-like cells and promoting the expression of cardiomyocyte structural proteins, ultimately inducing the differentiation of bone marrow mesenchymal stem cells into cardiomyocyte-like cells. Stem cell factor (SCF) in bone marrow mesenchymal stem cells is a possible chemotactic factor that plays an important role in the migration, accumulation, and expansion of primitive bone marrow cells toward the infarct area. Different concentrations of Sal B can significantly promote the secretion of SCF by bone marrow mesenchymal stem cells and enhance the expression of SCF mRNA. Experiments using Sal B to pretreat endothelial progenitor cells and bone marrow mesenchymal stem cells have shown that Sal B can increase the proliferation, adhesion, and migration capabilities of endothelial progenitor cells, promote the formation of new blood vessels, improve the myocardial microenvironment, and upregulate the expression of NKX2.5 and GATA-4 genes, thereby enhancing the targeted differentiation of bone marrow mesenchymal stem cells into cardiomyocytes.

In addition, research results indicate that the protective effect of Sal B on ischemia-reperfusion hearts is also related to activating endogenous protective mechanisms. Using a hypoxia model of human umbilical vein endothelial cells (HUVECs), studies have confirmed that Sal B magnesium salt can protect endothelial cells by inhibiting NO release and the increase in eNOS mRNA expression, as well as by antagonizing Ca2+ influx. In a H2O2-induced injury model of HUVECs, Sal B inhibits the expression of CD54 in endothelial cells in a dose-dependent manner, reducing the adhesion rate of neutrophils. Moreover, Sal B can upregulate the endoplasmic reticulum stress-related protein, glucose-regulated protein 78 (GRP78), thereby preventing oxidative stress-induced injury to HUVECs. This effect is associated with the activation of the ATF6 and PERK-eIF 2α-ATF4 pathways.

6.Anti-Atherosclerotic Effects

Sal B has been shown to inhibit the upregulation of MMP-2, MMP-9, and COX expression in human aortic smooth muscle cells (HASMCs) induced by various factors. In vitro experiments have also confirmed that Sal B can reduce the thickening of the aortic intima. Using human aortic endothelial cells (HAECs), the effects of Sal B on the expression of cell adhesion molecules were studied. The results showed that both the aqueous extract of Danshen and Sal B significantly reduced the expression of VCAM-1 and ICAM-1, decreased the binding of human monocyte line U937 to TNF-α-treated HAECs, and inhibited the activation of NF-κB in TNF-α-induced HAECs. The anti-inflammatory properties of Sal B provide new evidence for elucidating its anti-atherosclerotic effects. Additionally, research has found that Sal B can scavenge free radicals in circulation, reduce the consumption of vitamin E, and indirectly prevent the oxidative modification of LDL, thereby delaying the progression of atherosclerosis.

In addition, Sal B can upregulate the expression of tissue-type plasminogen activator (t-PA) and thrombomodulin (TM) in HUVECs, and downregulate the expression of plasminogen activator inhibitor-1 (PAI-1), thereby enhancing the fibrinolytic activity of HUVECs. Research has found that Sal B inhibits the expression of PAI-1 in TNF-α-induced HUVECs in a time- and dose-dependent manner. This effect is related to the NF-κB and ERK-AP1 signaling pathways. These data suggest that Sal B can alter the gene expression of endothelial cells, prevent vascular events, and has promising applications in the prevention and treatment of thrombotic diseases.

The occurrence of atherosclerosis is also related to the adhesion and aggregation of platelets. Sal B counteracts platelet adhesion by inhibiting the release of various mediators from platelets and/or preventing the binding of collagen-related receptors on platelets to collagen. Further research has found that Sal B can inhibit platelet deposition on the specific peptide α2β1, specifically inhibit the binding of anti-α2β1 antibodies to platelets, and prevent the soluble α2β1 from binding to each other to form insoluble collagen.

7.Vasodilatory Effects

The vasodilatory effects of the aqueous extract of Danshen and Sal B are mainly related to the inhibition of L-type voltage-dependent Ca2+ channels. The strong vasodilatory effect of Sal B and its high content in the aqueous extract of Danshen suggest that Sal B is an important component of Danshen in exerting vasodilatory effects. In both physiological and pathological states, Ca2+-activated K+ channels (BKCa) and ATP-dependent K+ channels (IKATP) play crucial roles in regulating coronary artery tension. Studies have shown that only Sal B among the crude extracts of Danshen can activate guanylate cyclase and induce the opening of BKCa channels in smooth muscle cells.

References:

[1] Wei Xiyu, Yang Ting, Liu Hourang, et al. Research Progress on the Pharmacological Effects of Salvianolic Acid B [J]. Pharmaceutical Research, 2021, 40(11): 748-752.

[2] Lin Chao, Liu Zhaoguo, Qian Xing, et al. Research Progress on the Pharmacological Effects of Salvianolic Acid B in Cardiovascular Diseases [J]. Chinese Pharmacological Bulletin, 2015, 31(04): 449-452.

[3] Wang Yun. Research Progress on the Pharmacological Effects of Salvianolic Acid B on Cardiovascular and Cerebrovascular Diseases [J]. Modern Journal of Integrated Traditional Chinese and Western Medicine, 2010, 19(35): 4634-4637.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.