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A recent article published in this journal, entitled “The influence of herbal medicine on platelet function and coagulation: a narrative review,” byMcEwen,1 nicely reviewed how herbal medicines can play a role in modifying cardiovascular diseases (CVDs), and also highlighted the interaction of herbal medicines with standard anticoagulant medicinal therapy. Here, we wish to further reflect on the effects of Danshen on the cardiovascular system, and also to report the novel underlying mechanism of its main constituents on platelets function and hemostasis. To our knowledge, these aspects have not been previously fully described. CVDs are the main causes of morbidity and mortality worldwide.2 They include myocardial infarction, stroke, rheumatic heart disease, and also peripheral artery disease and venous thrombosis.3 The underlying mechanisms diverge depending on the disease in question.4 Scientists working on CVDsagree that inmost cases hyper-platelet aggregation seems to be a crucial step in cardiovascular hemostasis and in the development and progression of CVDs. For these reasons, pharmacological therapies with agents that modulate platelet reactivity have proven to be effective in the treatment and/or in the prevention of CVDs.5 Moreover, advancements in technology and better knowledge of both platelet biology and biological functions of natural products have facilitated this process and pushed researchers to search for new and more reliable targets. Finally, but not less important, research into natural compounds founded on their ethnopharmacological information, has provided significant contributions to drug improvement and has paved the way for new pharmacological tools.6 Danshen has beenwidely used in traditional folk medicine in China and, to a lesser extent,within theUnited States and several European countries to treat CVDs and cerebrovascular diseases.7 Its cardiovascular beneficial actions are attributable to “thinning” the blood and reducing blood clotting, as well as to “invigorate” theblood or improve circulation. AlthoughDanshen is officially listed in the Chinese Pharmacopeia, the cardiovascular pharmacology of its active constituents has not yet been fully described. To date, more than 40 lipophilic tanshinones and 50 hydrophilic phenolics-like compounds have been isolated from Danshen root and extensively investigated for their cardiovascular activities.8 If we had to promote an “ideal candidate” from one of these lipophilic/phenolics-like compounds in the context of CVDs, this would be without any doubt tanshinone IIA (TIIA) and cryptotanshinone (CRY). Indeed, the discovery of these derivatives of phenanthrene-quinone isolated from Danshen have completely changed the way we look at many Danshen-mediated pharmacological properties.9 Recently, the pharmacological properties of TIIA andCRY in the cardiovascular systemhave attractedgreat interest. Emerging experimental studies and clinical trials have demonstrated that both the compounds prevent atherosclerosis and atherogenesis, as well as cardiac injury due the pleiotropic inhibition of low-density lipoprotein oxidation, monocyte adhesion to endothelium, smooth muscle cell migration and proliferation, macrophage cholesterol accumulation, and proinflammatory cytokine production.10,11 Moreover, few but representative studies have reported the effects of Danshen and TIIA on human blood platelets, human cardiomyocytes and vascular endothelial cells.12–14 However, no preclinical studies and clinical evidences have as yet underlined the key role of TIIA and CRY on platelet biology. A recent article15 has changed this scenario showing that TIIA in vitro selectively inhibited rat platelet aggregation induced by reversible adenosine diphosphate (ADP) stimuli (3 μM) in a concentration-dependent manner (0.5–50 μM). Nevertheless, TIIA was less active against the irreversible stimuli induced by ADP (10 μM) and collagen (10 μg/mL). Moreover, experiments performed on platelet lysates collected at different time-point after the addition of the stimuli shown that TIIA modulated tubulin acetylation and inhibited Erk-2 phosphorylation. Concomitantly, TIIA administrated intraperitoneally at 10 mg/kg significantly prolonged the Letter to the Editor

Danshen and the Cardiovascular System: New Advances for an Old Remedy