## 5 Bioactivity of Secondary Metabolites in the _Leontopodium_ Taxa
### Angiogenic and Cardioprotective Bioactivity  
The recovery after myocardial infarction (MI) is affected by insufficient angiogenesis and arteriogenesis. The myocardium has only limited regenerative abilities, and, in MI, the lost myocardial mass is replaced with fibrous tissue. As a compensatory mechanism for the loss of muscular mass through cardiomyocyte necrosis and apoptosis, the remaining myocardium increases its mass through cardiomyocyte hypertrophy and tissue remodelling processes (e.g., left ventricular dilatation). In allopathic therapy, complications associated with coronary arterial bypass grafts (neointima formation, hyperplasia and atherosclerosis) are treated with chemotherapeutics or immunosuppressive agents but with partial efficiency and adverse effects [106]. As an alternative treatment, natural compounds able to stimulate angiogenesis can be used. One of the promising compounds used for an improvement in ventricular function and the stimulation of angiogenesis and arteriogenesis was leoligin, a furan-type lignan identified in _L. alpinum_ root extract [10; 11]. In one of the first studies on this subject, the inhibitory effect of leoligin on the endothelial intimal hyperplasia after arterial bypass grafting was studied using mice or in vitro human saphenous vein organ cultures as model systems [10] (Table 2). Leoligin presented anti-hyperplasic activity, inhibiting the proliferation of vascular smooth cells through the induction of cell cycle arrest in the G1 phase, but did not induce cell death in smooth muscle and endothelial cells [107]. A leoligin derivative, 5-methoxyelogin, was able to induce angiogenesis by upregulating _CYP26B1_, which encodes a cytochrome P450 protein, in HUVECs and stimulated arteriogenesis in an in vivo rat model with myocardial infarction [89]. The same authors demonstrated that the compound 5-methoxyelogin stimulated capillary tube formation, in vitro angiogenic sprouting and angiogenesis in a chicken chorioallantoic membrane assay and induced a higher regeneration rate of arterioles in the peri-infarction and infarction areas, reducing myocardial muscle loss and promoting a significant increase in the left ventricular function, in a study using an animal model [89]. Another activity of leoligin on the cardiovascular system showed that higher doses than 1 mM inhibited the cholesteryl ester transfer protein (CETP) [10]; therefore, this compound could be used against coronary artery disease. A series of subsequent studies on lipoprotein metabolism proved that leoligin could be a promising candidate for counteracting atherosclerosis. Leoligin affected the CETP level in rabbit and human plasma [108], and through the inhibition of 3-hydroxy-methyl-glutaryl-CoA reductase, cholesterol levels can decrease in hyperlipidaemic (ApoE\({}^{//}\)) mice [105]. Another study showed that leoligin induced cholesterol efflux in THP-1-derived macrophages (a human leukaemia monocytic cell line) by upregulating _ABCA1_ and _ABCG1_ expression [109]. These genes encode for receptor-dependent cholesterol efflux through ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1), which are the predominant transporter-mediated cholesterol in human macrophages. Also, proteome analyses revealed the modulation of protein expression fingerprints in the presence of leoligin. Due to the spectacular pharmacological profile of this lignin and its methoxy derivative, recent studies aimed to create synthetic derivatives with improved bioactive properties, such as NF-kB inhibitory agents [110; 111], selective inhibitors of the proliferation of vascular smooth muscle cells [110; 112], antagonists for the Farnesoid X receptor to block cholesterol uptake in intestinal cells [113] or synthetic ligands with the potential to promote cholesterol efflux from macrophages [114]. Leoligin, known to inhibit intimal hyperplasia and the regrowth of endothelial cells, was exploited along with several structural analogues