Simvastatin and GGTI-2133, a geranylgeranyl transferase inhibitor, increase erythrocyte deformability but reduce low O₂tension-induced ATP release

Abstract

Statin drugs inhibit 3-hydroxy-3-methylglutaryl CoA reductase, which reduces the synthesis of both cholesterol and isoprenoids (geranylgeranyl pyrophosphate and farnesyl pyrophosphate), with the latter being lipid molecules responsible for the posttranslational modification of small GTP-binding proteins such as Rho. Effects of statins, independent of lowering blood cholesterol levels, are thought to occur by inhibition of Rho/Rho kinase. The Rho kinase inhibitor Y-27632 has been reported to increase both erythrocyte deformability and low O2 tension-induced ATP release. Here, we tested the hypothesis that by inhibiting Rho/Rho kinase, simvastatin would increase both erythrocyte deformability and low O2 tension-induced ATP release. Male Sprague-Dawley rats were divided into two groups, control or simvastatin treated [simvastatin-supplemented chow (0.02%)], for 4 wk. Simvastatin treatment increased rat erythrocyte deformability compared with controls (n = 6, P < 0.05). However, erythrocytes of simvastatin-treated rats (n = 9, P < 0.05) exhibited impaired low O2 tension-induced ATP release. Similarly, the geranylgeranyl transferase inhibitor GGTI-2133 (10 μM) also increased deformability and impaired low O2 tension-induced ATP release in healthy human erythrocytes (P < 0.05). Interestingly, ATP release in response to mastoparan 7 (n = 7, P < 0.05), which directly activates Gi, and isoproterenol (n = 5, P < 0.05), which signals through Gs, was not altered by incubation with GGTI-2133. These results suggest that although statins increase erythrocyte deformability, likely by inhibiting geranylgeranylation, the finding that both statins and a geranylgeranyl transferase inhibitor attenuated low O2 tension-induced ATP release demonstrates that factors in addition to erythrocyte deformability are critical for ATP release in response to this physiological stimulus.

Plasmodium falciparum ligand binding to erythrocytes induce alterations in deformability essential for invasion

“…To identify the kinase(s) involved in erythrocyte phosphorylation triggered by EBA-175 RII binding to GPA we tested erythrocyte kinase inhibitors that influence erythrocyte deformability. A protein kinase C (PKC) inhibitor, Gö9676 ( Bailey et al, 2014 ), four transient receptor potential cation channel (TRPM7) inhibitors, FTY720, sphingosine ( Qin et al, 2013 ), waixenicin A ( Zierler et al, 2011 ) and NS8593 ( Chubanov et al., 2012 ), three Rho-kinase inhibitors, Y-27632 ( Ruef et al, 2011 ), simvastatin ( Clapp et al, 2013 ) and HA1077-fasudil ( Tiftik et al, 2014 ), an adenylyl cyclase and protein kinase A (PKA) stimulator, forskolin ( Muravyov and Tikhomirova, 2013 ), an AMP-activated PK inhibitor, dorsomorphin ( Liu et al, 2014 ), a phosphodiesterase inhibitor, isobutyl-methyl-xantine (IBMX, [ Muravyov and Tikhomirova, 2013 ]), a spleen tyrosine kinase (syk) inhibitor, BAY-3606 ( Norman, 2014 ), a Ca 2+ channel inhibitor, verapamil ( Ruef et al, 2011 ) and three inhibitors of mechanically activated currents through channels such as TRPM7 or Piezo1, gadolinium (III), ruthenium red ( Drew et al, 2002 ) and GsMTx-4 ( Dorovkov et al, 2008 ). Some inhibitors had no effect on overall growth of P. falciparum whilst others reduced it to less than 50% compared to controls (sphingosine, Y-27632, IBMX, BAY61-3606, gadolinium (III) and verapamil) ( Figure 3A ).…”

Reduced deformability contributes to impaired deoxygenation‐induced ATP release from red blood cells of older adult humans

“…RBC deformability was measured using the St George's blood filtrometer (Carri-Med, Dorking, UK) (Sprague et al 1996(Sprague et al , 1998(Sprague et al , 2001aOlearczyk et al 2004a;Sridharan et al 2010b;Thuet et al 2011;Clapp et al 2013;Richards et al 2014). This device develops a calibrated 3 cmH 2 O pressure gradient across a vertically mounted, 13 mm diameter polycarbonate filter (Nucleopore, Whatman, GE Healthcare, Pittsburgh, PA, USA) with 9.53 mm exposed surface diameter and average pore size of 5 µm compared to the average RBC size of ß6-8 µM (thus, RBCs must deform to pass through the filter).…”

Poorly controlled type 2 diabetes is accompanied by significant morphological and ultrastructural changes in both erythrocytes and in thrombin-generated fibrin: implications for diagnostics

“… An increase in glycolysis metabolite concentrations and glucose-6-phosphate dehydrogenase activity in rat RBCs [ 114 ]. Increased erythrocyte fluidity [ 115 , 116 ] and deformability [ 100 , 117 ]. Reversed alteration in RBC plasma membrane properties, including lipid peroxidation [ 101 , 118 ].…”