A Clinical Evaluation of Statin Pleiotropy: Statins Selectively and Dose-Dependently Reduce Vascular Inflammation

Abstract

Statins are thought to reduce vascular inflammation through lipid independent mechanisms. Evaluation of such an effect in atherosclerotic disease is complicated by simultaneous effects on lipid metabolism. Abdominal aortic aneurysms (AAA) are part of the atherosclerotic spectrum of diseases. Unlike atherosclerotic occlusive disease, AAA is not lipid driven, thus allowing direct evaluation of putative anti-inflammatory effects. The anti-inflammatory potency of increasing doses (0, 20 or 40 mg/day) simvastatin or atorvastatin was evaluated in 63 patients that were at least 6 weeks on statin therapy and who underwent open AAA repair. A comprehensive analysis using immunohistochemistry, mRNA and protein analyses was applied on aortic wall samples collected during surgery. The effect of statins on AAA growth was analyzed in a separate prospective study in incorporating 142 patients. Both statins equally effectively and dose-dependently reduced aortic wall expression of NFκB regulated mediators (i.e. IL-6 (P<0.001) and MCP-1 (P<0.001)); shifted macrophage polarization towards a M2 phenotype (P<0.0003); selectively reduced macrophage-related markers such as cathepsin K and S (P<0.009 and 0.0027 respectively), and ALOX5 (P<0.0009), and reduced vascular wall NFκB activity (40 mg/day group, P<0.016). No effect was found on other cell types. Evaluation of the clinical efficacy of statins to reduce AAA progression did not indicate an effect of statins on aneurysm growth (P<0.337). Hence, in the context of AAA the clinical relevance of statins pleiotropy appears minimal.

Activation of the vitamin D receptor selectively interferes with calcineurin-mediated inflammation: a clinical evaluation in the abdominal aortic aneurysm

“…Similarly, it was found that statins dose dependently reduce NFκB-driven inflammation in the aneurysm wall. 28 Lacking clear effects on other inflammatory pathways, VDR activation appears highly selectively influencing NFAT-mediated inflammation. Our observations not necessary exclude an effect of VDR activation on other pathways as reported in experimental studies.…”

“…Table 2 Relative mRNA expression of selected inflammatory mediators, proteases, cytokines, and cell activation markers (log transcript level relative to GAPDH (GAPDH = 0)) Vitamin D receptor activation and vascular inflammation AJ Nieuwland et al A critical point is whether the observed effects of VDR activation are beneficial in the context of AAA disease or vascular disease in general (atherosclerosis). Although cathepsin K 29 and L 30 have both been implicated in the process of aneurysm formation, 31 an apparent dominant role in AAA progression is challenged by the observation that reductions in cathepsin K and L expression during, respectively, statin 28 and ACE inhibitor therapy 27 are not followed by an effect on aneurysms growth. It is unclear whether and if the effects of VDR activation on T-helper cell content will influence AAA disease.…”

“…We cannot exclude that minor effects on other inflammatory pathways are missed due to a type II statistical error. Yet, if such effects exist, they presumably compare weakly with the effect exerted on the NFAT pathways, and with pleiotropic effects on NFκB and AP-1 signaling exerted by, respectively, statins 28 and ACE inhibitors, 27 and doxycycline. 26 A further limitation of the study is that evaluation of baseline vitamin D status was not included in the study protocol.…”

Ace inhibitors potently reduce vascular inflammation, results of an open proof-of-concept study in the abdominal aortic aneurysm

“…The validity of the concept has been previously proven for compounds such as statins and doxycycline. [21,25] In this study we evaluated the potential of ramipril, one of more lipophilic members of the ACE-inhibitor family. This compound was chosen for its preclinical efficacy and its superior tissue penetration [26,27].…”

“…Double staining for CD68/HLA-DR (human leukocyte antigen DR; clone TAL.1B5, 1:1000 dilution, DakoCytomation) was performed in order to assess macrophage activation. [18][19][20][21] The double-stainings were quantified by counting the number of double positive cells in six representative medium power fields (two photographs for each vascular layer) by two independent blinded observers. There was high inter observer reliability for the CD68-CD163, CD68-iNOS, and CD68-HLADR (a50.916, a50.875, a50.839, respectively).…”