Effects of pitavastatin on monocyte chemoattractant protein-1 in hyperlipidemic patients

Abstract

The effects of statins on platelet activation markers, chemokines and adiponectin, were investigated in 135 patients with hyperlipidemia. Of the 135 hyperlipidemic patients, 63 were allocated to the simvastatin group, treated with simvastatin at the dose of 10 mg daily, and the remaining 72 were allocated to the pitavastatin group, treated with pitavastatin at the dose of 2 mg daily. Plasma levels of platelet-derived microparticles (PDMP), cell adhesion molecules (sCD40L and sP-selectin), chemokines [monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normally T-cell expressed and secreted] and adiponectin were measured at the baseline and after 6 months of treatment in both the groups. In addition, we carried out a basic study to investigate the MCP-1-dependent induction of tissue factor expression on a histiocytic cell line (U937 cells). The plasma levels of PDMP, sCD40L, sP-selectin, regulated on activation normally T-cell expressed and secreted and MCP-1 were higher, whereas those of adiponectin were lower, in the hyperlipidemic patients than in the normolipidemic controls. Plasma PDMP and sCD40L were positively correlated, whereas plasma adiponectin was negatively correlated, with the plasma levels of MCP-1. No significant differences in the plasma levels of PDMP, sCD40L, sP-selectin, regulated on activation normally T-cell expressed and secreted and MCP-1 measured before and after treatment were observed in either the simvastatin or pitavastatin group. A significant increase of the plasma adiponectin levels was observed after 6 months of treatment with pitavastatin but not after an equal duration of treatment with simvastatin. When pitavastatin-treated patients were divided into two groups according to the adiponectin response to pitavastatin treatment, significant decreases of the plasma MCP-1, PDMP and sCD40L levels were observed after pitavastatin treatment in the responder group. In the aforementioned basic study, MCP-1 by itself did not induce the expression of tissue factor on the U937 cells. However, the recombinant sCD40L-induced expression of tissue factor on U937 was enhanced by the addition of MCP-1. These findings suggest that PDMP, sCD40L and MCP-1 may participate in the development of atherothrombosis in patients with hyperlipidemia and that pitavastatin may exert an adiponectin-dependent antiatherothrombotic effect in hyperlipidemic patients.

Pharmacological effects of lipid-lowering drugs on circulating adipokines

“…Adiponectin increased in response to pitavastatin but not in response to simvastatin [74] Humans with increased cardiovascular risk 12 wk of 10-80 mg/d atorvastatin Adiponectin increased by 10% with maximal increase (25%) observed at 80 mg/d (P < 0.05) [75] Humans with hypercholesterolemia and CAD b 6 mo of 10-20 mg/d pravastatin Adiponectin increased by 16.8% from 7.2 to 7.8 µg/mL (P < 0.001) [76] Humans with hypercholesterolemia and ischemic heart disease 3 mo of 10 mg/d atorvastatin Adiponectin increased from 9.7 ± 7.4 to 13.9 ± 9.98 µg/mL (P < 0.005) [77] C57BL/6J mice 0-15 wk of 0.06% of diet as pravastatin…”

“…Indeed, atorvastatin increased plasma adiponectin levels in men with hypercholesterolemia and increased adiponectin production and secretion in 3T3-L1 adipocytes [78] . Conversely, other studies examining the effects of simvastatin demonstrated that adiponectin concentrations were either unchanged [74,81] or reduced [82][83][84][85] . Nomura and colleagues tested the effects of either pitavastatin or simvastatin in humans with hypercholesterolemia and found that plasma total adiponectin concentrations increased after six months of pitavastatin treatment, but were unaffected by simvastatin [74] .…”

“…Conversely, other studies examining the effects of simvastatin demonstrated that adiponectin concentrations were either unchanged [74,81] or reduced [82][83][84][85] . Nomura and colleagues tested the effects of either pitavastatin or simvastatin in humans with hypercholesterolemia and found that plasma total adiponectin concentrations increased after six months of pitavastatin treatment, but were unaffected by simvastatin [74] . Koh et al [85] compared pravastatin therapy to simvastatin therapy in hypercholesterolemic patients and found that pravastatin increased while simvastatin decreased plasma adiponectin concentrations.…”

“…Additional studies utilizing simvastatin [74] , pravastatin [21] , fluvastatin [91] or atorvastatin [92][93][94] in a variety of subjects (healthy humans, humans with hypercholesterolemia or hyperlipoproteinemia or kidney transplant recipients) all found no change in circulating adiponectin concentrations in response to statin treatment. A possible explanation for this discrepancy may involve the analysis of the different multimers of adiponectin.…”

“…Adiponectin also directly improves endothelial dysfunction by stimulating production of nitric oxide [70] , inhibiting proliferation of vascular smooth muscle cells [71,72] , and inhibiting the conversion of macrophages to foam cells [73] . Evidence suggests that serum adiponectin concentrations increase in response to atorvastatin, pitavastatin and pravastatin (Table 1) [22,[74][75][76][77][78][79][80] . Indeed, atorvastatin increased plasma adiponectin levels in men with hypercholesterolemia and increased adiponectin production and secretion in 3T3-L1 adipocytes [78] .…”