Cardiovascular disease and cancer are independent leading causes of morbidity and mortality worldwide, seriously threatening human health and quality of life. With increase in the incidence of both cardiovascular disease, such as myocardial ischemia and cancer, the number of patients simultaneously laden with cardiovascular disease and malignant tumor is increased, and these complex pathological conditions pose greater challenge for clinical treatment. Moreover, anti-cancer agents or chemotherapies cause cardiovascular side effects including myocardial ischemia. Therefore, it remains as a research focus to develop therapies that present effective management of both cardiovascular disease and tumor when both conditions are coexistent in a particular patient.
It is a well-established concept that angiogenesis plays crucial roles in the pathogenesis of various diseases including tumor growth and progression and myocardial ischemia . Enhanced or excessive angiogenesis is commonly observed in tumor whereas defective or insufficient angiogenesis is one of the essential pathological features implicated in myocardial ischemia. Therefore, anti-angiogenic therapy has been considered as a new modality for tumor treatment. On the other hand, treatment promoting angiogenesis is recognized as an important strategy to enhance the clinical management of myocardial ischemia .
Notoginseng is a one of the most extensively used medicinal herb that has a long history of clinical utilization in treating various diseases either by itself or in combination with other natural products in Traditional Chinese Medicine (TCM) . The major active components of notoginseng are panax notoginseng saponins (PNS), which consist of more than 30 different types of saponins, among which ginsenoside Rg1, Rb1 are found in high content and notoginsenoside R1 a component unique to notoginseng . PNS has been widely adopted as a therapeutic agent for treating cardiovascular diseases in clinic under the guidance of TCM theory . Experimental evidences have been presented indicating that the cardiovascular benefits of PNS are mediated through diverse mechanisms including alleviating oxidative stress, promoting angiogenesis, modifying vasomotor function, reducing platelet adhesion, modulating ion channels, altering autonomic neurotransmitters release, and improving lipid profiles, etc . Each component of PNS may exert different pharmacological effects underlined by varied mechanisms. Independent studies have shown that PNS could stimulate HUVEC proliferation, increase the numbers of invaded cells and tube branches and promote changes in the subintestinal vessels in zebrafish, supporting that PNS are equipped with proangiogenic functions . Ginsenoside Rg1 has been noted as a stable proangiogenic agent in that HUVEC proliferation, migration and tube formation were significantly enhanced in the presence of Rg1 in vitro, and the density of newly formed vessels in the animals receiving Rg1 treatment witnessed significantly increase as well . On the other hand, ginsenoside Rb1 exhibits inhibitory effects on proliferation and tube-like structure formation of endothelial cells in vitro [9, 10]. Notoginsenoside R1 instead has been shown to be a promising compound for protecting the heart from septic shock and has anti-inflammatory effects in mice .
Additionally, PNS and its major components exhibit anticancer activities and have been shown to be effective against a variety of malignancies, for instance, colorectal, lung, gastric, skin, prostate and liver cancer . It has been shown that PNS, Rg1, Rb1 or R1 display antiproliferative activities in tumor cells . Whether or not PNS, Rg1, Rb1 or R1 exert anti-angiogenesis effects in the context of tumor growth and progression remains to be evaluated. Furthermore, whether PNS, Rg1, Rb1 or R1 could simultaneously exert proangiogenic and antiangiogenic effect when myocardial ischemia is complexed with tumor is unknown.
To address this, we established the model of lewis lung carcinoma coupled with myocardial ischemia in mouse, and investigated the effects of PNS and its major activity components Rg1, Rb1 or R1 on the tumor growth and myocardial ischemia in this complex model. We further evaluated the impact of PNS, Rg1, Rb1 or R1 on the angiogenic events and associated miR expression in tumor and heart in this complex model. Our results for the first time demonstrated a bidirectional regulatory effect of PNS on angiogenesis under complex disease conditions such as tumor coupled with myocardial ischemia, which may contribute to the simultaneous effects of PNS on suppressing tumor growth and alleviating myocardial ischemic injuries. Our data further suggest that this bidirectional effect of PNS on angiogenesis in vivo could be achieved through tissue specific modulation of the expression of proangiogenic miR-18.