Statins- existing treatments for atherosclerosis
Statins or 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are lipid lowering drugs and used in the treatment of hypercholesterolemia, which is a main contributor to cardiovascular disease and thus morbidity and mortality rates. Statins are one of the most widely used exsisting treatments for atherosclerosis. Many clinical trials such as the Scandinavian Simvastatin Survival Study (4S) and Cholesterol and Recurrent Events (CARE) have demonstrated the positive effect of statin therapy (Liao and Laufs, 2005).
Statins are used as both primary and secondary preventatives of arterial disease and their pleiotrophic effects on cellular functions and signalling in inflammatory associated sites (Iwata et al., 2012). As excess cholesterol impairs endothelial production and increases nitric oxide degradation, the administration of statins also improves endothelial function.
How statins function
Statins function by inhibiting the enzyme HMG-CoA reductase which is responsible for catalyzing the conversion of HMG-CoA to mevalonic acid in cholesterol biosynthesis. A reduction of circulating cholesterol triggers an increase in LDL receptor expression which facilitates clearance of LDL and LDL precursors. Statins also play a minor role in elevating HDL levels (Maron et al., 2000, LaRosa et al., 1999). Statins stimulate and upregulate the enzyme endothelial NO synthase (eNOS) which increases NO production. In hypoxic and hyperlipidemia conditions statins also restore eNOS activity and prevents further endothelial dysfunction (Liao and Laufs, 2005).
Statins activate the PI3K/Akt pathway which induces endothelial progenitor cell (EPC) differentiation. These discoveries lead to a therapeutic goal of rescuing tissue from critical ischemia by stimulation of neovascularization (Dimmeler et al. 2001).
Other indirect beneficial roles that statins are involved in include decreasing SMC production in vitro and studies have shown simvastatin and pravastatin specifically reduce macrophage proliferation. Macrophages degrade collagen which is the structural backbone of the fibrous cap (Liao and Laufs, 2005). In general and unrelated to cholesterol metabolism, statins protect against plaque progression and rupture by inhibiting lymphocyte and other blood mononuclear cell growth (Maron et al., 2000).
Statins also affect plasminogen activator inhibitor -1 and fibrinogen levels and pravastatin lowers C-reactive protein levels. Studies have suggested statins as anti-inflammatory drugs, the mechanisms involved in reducing the number of inflammatory cells have yet to be elucidated but they possess the ability to inhibit adhesion molecule expression (ICAM-1) (Liao and Laufs, 2005).
Lipid related targeting
New and old trials remain constant in emphasizing the importance of lowering and overall clearance of LDL in high risk patients. Emerging treatments such as PCSK9 inhibitors key target is LDL. The role of HDL is less clear, the emerging risk factor collaboration have provided robust data on HDL as an undisputable risk factor for CVD (Chong and Bachenheimer, 2000). To date there are still no clinical trials supporting the theory that targeting HDL will reduce CV outcome. Using novel biomarkers and pharmacogenomics approaches are ongoing to help improve therapeutics for dyslipidemia management (EAS report 2013).
Nuclear receptors, liver X receptors (LXRs) are activated by oxysterols and play an important role in controlling lipid homeostasis, specifically in regulating cholesterol and fatty acid metabolism in macrophages. As dyslipidemia is a main risk factor in atherosclerosis these receptors play an influential role in disease progression. Studies have shown correlation between LXR activity and the pathogenesis of atherosclerosis which suggests it could be an attractive target for therapeutics (Joesph and Tontonoz, 2003). However there has only been one phase 1 study so far in humans. The non-specific LXR agonist increased efflux pathways ABCG1 and ABCA1 (Laurencikiene and Ryden, 2012).
Up and coming therapeutics
Endothelial damage evolution and severity in advanced atheroma remains elusive, partly due to a lack of in vivo quantifiable methods. Recently endothelial damage was quantified in an ApoE deficient mouse model using a multifunctional perfluorocarbon nanoparticle (PFC NP). It concluded that endothelium damage correlated with the length of the animal-fat diet consumption. The model also investigated PFC NP as a drug deliverer, loading the particle with a nf-kb inhibitor reduced inflammation (Pant et al., 2013).
Activation of NOX proteins, a new NADPH oxidase subfamily, signal through MAPK, tyrosine kinases and transcription factors to stimulate ROS production. ROS plays a pathophysiological role in inflammation, endothelial dysfunction, hypertrophy and angiogenesis (Cai et al., 2003). Therapeutics against NADPH oxidases have the ability to lower ROS levels and potentially protect against vascular injury (Paravicini and Touyz, 2008).
Cell based therapeutics
Foam cells are an essential requirement in all stages of the pathogenesis of atherosclerosis. Studies elucidating cellular processes associated with macrophages have suggested numerous therapeutic targets such as, monocyte recruitment and cholesterol uptake and evacuation (Choudhury et al., 2005).