Never the Twain shall Meet: Statins and Oxysterols for Treating Comorbidities in Atherosclerotic Patients

Combining statins with the oxysterol, 25-hydroxycholesterol (25-HC) may enhance inflammation and therefore caution must be exercised due to to its synergistic role that promotes disease. Recent studies have shown that 25-HC impairs endothelial function, and the presence of oxysterols including 25-HC has been documented in mouse macrophage foam cells, and abundantly in human atherosclerotic plaques. 25-HC may play an active role in plaque development, by binding to the orphan receptor ligand, ORP4L. Excessive stimulation by 25-HC interferes with the OPR4L/Ga_q/11/PLCβ3 complex and block Ca²⁺ signaling, which results in macrophage apoptosis, consequently enhancing lesion progression, and risk of plaque rupture in advanced lesions. However, in early atherosclerotic lesions, the pro-apoptotic role of 25-HC may result in reduced macrophage numbers and thereby, decelerates plaque progression. As modulators of the sterol synthesis pathway, 25-HC has anti-inflammatory and anti-viral effects. The latter is effectuated by 25-HC, which targets viral entry and replication, by regulating the synthesis and compartmentalization of lipids on cell membranes. The enzyme cholesterol-25-hydroxylase (CH25H), expressed in innate immune cells such as macrophages, forms 25-HC from cholesterol and is transcriptionally upregulated by TLR activation, but not by interferons. Influenza virus infection upregulates CH25H in human airway epithelial cells, but is not essential for protection against viral infection, since 25-HC amplifies inflammatory signaling cascades. Chronic hepatitis C virus (HCV) infection is a systemic disease that increases risk of cirrhosis and its complications with pathogenesis manifested through vascular damage. Since HCV infection can increase cardiovascular risk, eradication of HCV may improve cardiovascular outcomes. However, controversy exists with regard to whether there are associations between HCV infection and cardiovascular dysfunction, due to contrasting results. Irrespective of a causal nature of HCV infection in atherosclerosis, there is the need for safe, effective interferon-free therapies for treatment of HCV infection. Recent studies indicate that 25-HC inhibits HCV, a risk factor for carotid atherosclerosis. The question therefore, is whether 25-HC may be combined with statins as a treatment modality for atherosclerosis. This treatment modality in managing co-morbidities in atherosclerosis certainly needs careful and judicious consideration due to its likely antagonistic effect, rather than a synergistic one.