Ameliorating effects of compounds derived from Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion
Introduction
Ischemia and reperfusion (I/R) occurs in a wide range of situations, including trauma, vascular reflow after contraction, precutaneous transluminal coronary angioplasty, thrombolysis treatment, organ transplantation, and hypovolemic shock with resuscitation. I/R exerts multiple insults in microcirculation, frequently accompanied by endothelial cell injury, enhanced adhesion of leukocytes, macromolecular efflux, production of oxygen free radicals and mast cell degranulation (Han et al., 2001). Thus, much effort has been made to attenuate the microcirculatory disturbance by ablating one of the insults in the pathogenetic process. Preliminary results demonstrated that pretreatment with antibodies against adhesion molecules inhibits I/R-induced leukocyte adhesion to postcapillary venules (Kurose et al., 1994a), pretreatment with antioxidants inhibits I/R-induced oxygen free radical production, leukocyte adhesion to postcapillary venules and mast cell degranulation (Han et al., 2001) and pretreatment with mast cell degranulation inhibitors attenuated I/R-induced microcirculatory injury (Kurose et al., 1997). However, the outcomes of these attempts have been far from satisfactory to date. This is deemed to attribute to the observation that the microcirculatory disturbance is a complicated pathologic process consisting of multiple and coordinated events, and once this process has been initiated, it can be interrupted only by a remedy of multiple compositions targeting respectively at different insults causing the microcirculatory disturbance.
For several decades, Salvia miltiorrhiza root (Labiatae, Laminaceae; Fig. 1) has been widely used in clinics in China, Korea, Japan and other Asian countries for the treatment of various microcirculatory disturbance-related diseases, such as cardiovascular disease, cerebrovascular disease, liver dysfunction, renal deficiency and diabetic vascular complication. Chemical constituents from S. miltiorrhiza root extract (SMRE) are classified into 2 major categories: water-soluble compounds (WSC) and lipophilic diterpenoid quinines (LDQ), the compounds of both have been mostly identified and purified (Gu et al., 2004, Hu et al., 2005, Shi et al., 2005, Liu et al., 2006, Lv and Yao, 2006, Yang et al., 2006, Zhou et al., 2006a). The WSCs of SMRE are mainly phenolic acid compounds, including single phenolic acids and polyphenolic acids. Single phenolic acids include protocatechuic aldehyde (PAl), protocatechuic acid (PA), caffeic acid (CA), and 3,4-dihydroxyphenyl lactic acid (DLA, also called danshensu), whereas polyphenolic acids include rosmarinic acid (RA), lithospermic acid (LsA), salvianolic acid A (SalA), salvianolic acid B (SalB) (Fig. 2), and other salvianolic acids. The major LDQs of SMRE are tanshinone I (TsI), tanshinone IIA (TsIIA), tanshinone IIB (TsIIB), cryptotanshinone (CTs), tanshindiol C (TsC), 15,16-dihydrotanshinone I (15,16-DTsI), isotanshinone I (ITsI), isotanshinone II (ITsII; Fig. 3) and other tanshinones. The in vivo metabolic pathways of some constitutes of the WSCs have been elucidated (Zhang et al., 2005, Wu et al., 2006).
The biological actions of the compounds isolated from SMRE have been clarified over the last few years, and several lines of evidence have been accumulated indicating the diversity of the potentials of SMRE in attenuating microcirculatory disturbance, including antioxidation (Zhao et al., 1996, Wu et al., 1998, Liu et al., 2001, Soung et al., 2003, Lin et al., 2006b), inhibition of expression of adhesion molecules (Chen et al., 2001c, Ren et al., 2002, Ding et al., 2005a, Ling et al., 2005, Sieveking et al., 2005, Zhou et al., 2005), inhibition of platelet aggregation (Wu et al., 1996), inhibition of mast cell degranulation (Ryu et al., 1999, Choi and Kim, 2004), inhibition of apoptosis (Nakazawa et al., 2005, Lee et al., 2006b), amelioration of the injury of target organs, such as the heart (Sun et al., 2005, Chang et al., 2006, Zhang et al., 2006), brain (Lo et al., 2003, Koo et al., 2004), liver (Xing et al., 2005, Lee et al., 2006a, Lee et al., 2006b, Wan et al., 2006), kidneys (Kang et al., 2004, Chen and Wang, 2006) and lungs (Chen et al., 2003). Therefore, SMRE has emerged as a candidate for improving microcirculatory disturbance by acting on multiple targets. Some reviews already exist concerning the major ingredients of SMRE and preclinical results (Ji et al., 2000, Wu et al., 2004, Jiang et al., 2005, Wang et al., 2006c). This review will focus on the ameliorating effects of compounds derived from SMRE on microcirculatory disturbance and target organ injury induced by I/R.
Section snippets
Effects of compounds derived from SMRE on pathogenesis of microcirculatory disturbance induced by ischemia and reperfusion
I/R leads to several injurious responses in microcirculation, such as an enhanced oxygen free radical production from endothelial cells (Granger, 1988), increased expression levels of L-selectin in leukocytes (Redlin et al., 2001, Wei et al., 2005) and E-selectin in endothelial cells (Russell et al., 2000, Cassie et al., 2004), causing the rolling of leukocytes (Kurose et al., 1994a, Arndt et al., 1995), and increased expression levels of CD11b/CD18 in leukocytes and intercellular adhesion
Protection of heart
Cardiac muscles have abundant capillaries to meet the demands for oxygen and nutrients and to eliminate wastes generated in various metabolisms, which are particularly important for the heart as it beats all the time. I/R induces a cascade of reactions in the heart, namely, the activation of NF-κB and AP-1 via peroxides, resulting in the expression of ICAM-1 on endothelial cells (Fan et al., 2002) and the release of TNF-α, which induces leukocyte adhesion to the endothelium and the subsequent
Conclusion
- (1)
The DLA, SalA, SalB and WSF of SMRE exhibit an antioxidative effect, whereas PA1, SalA and SalB inhibit the expression of adhesion molecules. Because both SalA and SalB possess the same structure as that of DLA, it is reasonable to assume that among the WSCs, DLA is one of the major agents effective for the antioxidation and inhibiting expression of adhesion molecules, by which actions DLA, PAl, SalA and SalB protect or improve microcirculatory disturbance induced by I/R.
- (2)
As to the LDQs of SMRE,
Acknowledgments
This work was supported in part by the International Science and Technology Cooperation Project from the Ministry of Science and Technology of the People's Republic of China (2006DFA32340).
We would like to thank Ms. Gou Jun, Ms. Li Dan, Mr. Han Dong, and Dr. Man Xu for help in reference collection.
References (153)
- et al.
Salvia miltiorrhiza attenuates the changes in contraction and intracellular calcium induced by anoxia and reoxygenation in rat cardiomyocytes
Life Sci
(2003) - et al.
Ischemia/reperfusion induces the recruitment of leukocytes from whole blood under flow conditions
Free Radic Biol Med
(2004) - et al.
Protective effects of Danshensu from the aqueous extract of Salvia miltiorrhiza (Danshen) against homocysteine-induced endothelial dysfunction
Life Sci
(2004) - et al.
Inhibitory effect of caffeic acid analogues isolated from Salciae militiorrhizae radia againse 1, 1-diphenyl-2-picrylhydrazyl radical
Exp Toxicol Pathol
(1999) - et al.
Aqueous extract of Salvia miltiorrhiza attenuates increased endothelial permeability induced by tumor necrosis factor-alpha
Int Immunopharmacol
(2005) - et al.
Exogenous human recombinant interleukin-10 attenuates hindlimb ischemia-reperfusion injury
J Surg Res
(1997) - et al.
Reperfusion syndrome: relationship of coronary blood flow reserve to left ventricular function and infarct size
J Am Coll Cardiol
(2000) - et al.
Coronary reactivity to endothelin-1 during partial ischemia and reperfusion in anesthetized goats. Role of nitric oxide and prostanoids
Eur J Pharmacol
(2002) - et al.
Demonstration of the myocardial salvage effect of lithospermic acid B isolated from the aqueous extract of Salvia miltiorrhiza
Life Sci
(1993) - et al.
Ischemic preconditioning and methylprednisolone both equally reduce hepatic ischemia/reperfusion injury
Surgery
(2004)
Fingerprinting of Salvia miltiorrhiza Bunge by non-aqueous capillary electrophoresis compared with high-speed counter-current chromatography
J Chromatogr A
Filamin redistribution in an endothelial cell reoxygenation injury model
Free Radic Biol Med
Leukocyte adhesion and hepatic microvascular responses to intestinal ischemia/reperfusion in rats
Gastroenterology
Inflammation in stroke and focal cerebral ischemia
Surg Neurol
Comparison of cardioprotective effects using ramipril and DanShen for the treatment of acute myocardial infarction in rats
Life Sci
Inhibition of interleukin-12 and interferon-gamma production in immune cells by tanshinones from Salvia miltiorrhiza
Immunopharmacology
Lithospermic acid B isolated from Salvia miltiorrhiza ameliorates ischemia/reperfusion-induced renal injury in rats
Life Sci
Hepatocyte protection by a protease inhibitor against ischemia/reperfusion injury of human liver
J Am Coll Surg
Neuroprotective effects of tanshinones in transient focal cerebral ischemia in mice
Phytomedicine
Activation of the iberiotoxin-sensitive BKCa channels by salvianolic acid B of the porcine coronary artery smooth muscle cells
Eur J Pharmacol
Relaxant effects of danshen aqueous extract and its constituent danshensu on rat coronary artery are mediated by inhibition of calcium channels
Vascul Pharmacol
Protective mechanism of Salvia miltiorrhiza on carbon tetrachloride-induced acute hepatotoxicity in rats
J Pharmacol Sci
15,16-dihydrotanshinone I suppresses the activation of BV-2 cell, a murine microglia cell line, by lipopolysaccharide
Neurochem Int
Salvianolic acid B, an antioxidant from Salvia miltiorrhiza, prevents Abeta(25-35)-induced reduction in BPRP in PC12 cells
Biochem Biophys Res Commun
In vitro protective effects of salvianolic acid B on primary hepatocytes and hepatic stellate cells
J Ethnopharmacol
Protection of Salvia miltiorrhiza against aflatoxin-B1-induced hepatocarcinogenesis in Fischer 344 rats dual mechanisms involved
Life Sci
Superoxide anion as a marker of ischemia-reperfusion injury of the transplanted kidney
Transplant Proc
Role of TNF in mediating renal insufficiency following cardiac surgery: evidence of a postbypass cardiorenal syndrome
J Surg Res
ICAM-1 upregulation in distant tissues after hepatic ischemia/reperfusion: a clue to the mechanism of multiple organ failure
J Pediatr Surg
Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation
Blood
Salvia miltiorrhiza inhibits biliary obstruction-induced hepatocyte apoptosis by cytoplasmic sequestration of p53
Toxicol Appl Pharmacol
Neutrophils generate oxygen free radicals in rat mesenteric microcirculation after abdominal irradiation
Gastroenterology
Leukocyte-endothelial cell adhesion in a model of intestinal inflammation
Gut
Reperfusion injury
New Horiz
ORP150/HSP12A protects renal tubular epithelium from ischemia-induced cell death
FASEB J
Analysis of cardioprotective effects using purified Salvia miltiorrhiza extract on isolated rat hearts
J Pharmacol Sci
Magnesium lithospermate B ameliorates renal cortical microperfusion in rats
Acta Pharmacol Sin
Effect of Salvia miltiorrhiza Bunge injection on anticardiolipin antibody production induced by beta2 glycoprotein
Acta Pharmacol Sin
Inhibition of inducible nitric oxide synthase (iNOS) prevents lung neutrophil deposition and damage in burned rats
Shock
Salvianolic acid B attenuates VCAM-1 and ICAM-1 expression in TNF-alpha-treated human aortic endothelial cells
J Cell Biochem
Effects of Salvia miltiorrhiza extracts on rat hypoxic pulmonary hypertension, heme oxygenase-1 and nitric oxide synthase
Chin Med J (Engl)
Tanshinones inhibit mast cell degranulation by interfering with IgE receptor-mediated tyrosine phosphorylation of PLCgamma2 and MAPK
Planta Med
Apoptosis and inflammation in renal reperfusion injury
Transplantation
Aqueous extract of Salvia miltiorrhiza regulates adhesion molecule expression of tumor necrosis factor alpha-induced endothelial cells by blocking activation of nuclear factor kappaB
J Cardiovasc Pharmacol
Protective effects of salvianolic acid A against impairment of memory induced by cerebral ischemia-reperfusion in mice
Chin Med J (Engl)
Oxygen radicals trigger activation of NF-kappaB and AP-1 and upregulation of ICAM-1 in reperfused canine heart
Am J Physiol Heart Circ Physiol
Resident cardiac mast cells degranulate and release preformed TNF-alpha, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion
Circulation
Multiple organ injuries after abdominal high energy wounding in animals and the protective effect of antioxidants
Chin Med Sci J
IL-10 does not affect oxidative burst and expression of selected surface antigen on human blood phagocytes in vitro
Physiol Res
Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury
Am J Physiol
Cited by (323)
Potential of natural products in combination with arsenic trioxide: Investigating cardioprotective effects and mechanisms
2023, Biomedicine and PharmacotherapyDihydrotanshinone I preconditions myocardium against ischemic injury via PKM2 glutathionylation sensitive to ROS
2023, Acta Pharmaceutica Sinica BSalvianolic acid B and ferulic acid synergistically promote angiogenesis in HUVECs and zebrafish via regulating VEGF signaling
2022, Journal of Ethnopharmacology