LDL-C: Theoretical Behavior Analysis

LDL-C is considered a potent inflammatory motivator so decreasing its level and increasing HDL-C level can contribute to lowering inflammatory mediators [29- Libby and Aikawa, 2002, 30- Linsel-Nitschke and Tall, 2005]. Several strategies have been adopted to lower elevated plasma cholesterol. For example, statins represent the cornerstone LDL-C lowering therapy to maintain vascular health and reduce atherosclerotic cardiovascular events in patients at higher risk of cardiovascular diseases [31- Andrews et al., 2001, 32- März et al., 2003]. However, their main drawbacks are poor response, intolerance and persistence of residual cardiovascular risk [33- Pazzucconi et al., 1995]. This has emergently driven needs for new safer LDL-C lowering alternative
However, some synthetic CETP inhibitors have displayed lack of efficiency or off-target adverse cardiovascular events, independent on CETP inhibitory activity, increasing mortality rates. Therefore, their clinical development has been terminated [36- Barter et al., 2007, 37- Schwartz et al., 2012]. Of interest, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recently reported as an attractive and effective target for hypocholesterolemic therapies [38- Steinberg and Witztum, 2009]. It has been recently reported that inhibition of PCSK9 can effectively achieve further reduction of LDL-C level beyond statins, protecting against atherosclerotic cardiovascular diseases risk [39- Cohen et al., 2005, 40- Cohen et al., 2006]. PCSK9 protein, a member of PC family has been discovered in 2003. It is expressed in hepatocytes and secreted into plasma. PCSK9 protein binds to LDL receptors (LDLR), promoting their endosomal uptake and lysosomal breakdown. Thus, increased activity of this protein reduces LDLR number which, in turn, suppresses LDL-C removal from the circulation, raising its level [41- Seidah et al., 2003, 42- Zhang et al.,