Diabetes reduces bone marrow and circulating porcine endothelial progenitor cells, an effect ameliorated by atorvastatin and independent of cholesterol

Abstract

Bone marrow derived endothelial progenitor cells (EPCs) are early precursors of mature endothelial cells which replenish aging and damaged endothelial cells. The authors studied a diabetic swine model to determine if induction of DM adversely affects either bone marrow or circulating EPCs and whether a HMG-CoA reductase inhibitor (statin) improves development and recruitment of EPCs in the absence of cholesterol lowering. Streptozotocin was administered to Yorkshire pigs to induce DM. One month after induction, diabetic pigs were treated with atorvastatin (statin, n = 10), ezetimibe (n = 10) or untreated (n = 10) and evaluated for number of bone marrow and circulating EPCs and femoral artery endothelial function. There was no effect of either medication on cholesterol level. One month after induction of DM prior to administration of drugs, the number of bone marrow and circulating EPCs significantly decreased (P < 0.0001) compared to baseline. Three months after DM induction, the mean proportion of circulating EPCs significantly increased in the atorvastatin group, but not in the control or ezetimibe groups. The control group showed progressive reduction in percentage of flow mediated vasodilatation (no dilatation at 3 months) whereas the atorvastatin group and ezetimibe exhibited vasodilatation, 6% and 4% respectively. DM results in significant impairment of bone marrow and circulating EPCs as well as endothelial function. The effect is ameliorated, in part, by atorvastatin independent of its cholesterol lowering effect. These data suggest a model wherein accelerated atherosclerosis seen with DM may, in part, result from reduction in EPCs which may be ameliorated by treatment with a statin.

Specific Role of Impaired Glucose Metabolism and Diabetes Mellitus in Endothelial Progenitor Cell Characteristics and Function

“…In addition to their lipid-lowering effect, statins have many pleiotropic effects that may explain their cardiovascular benefit. Both experimental 81,82 and clinical studies 83 demonstrate that statins increase the number and function of circulating EPCs by increasing the bioavailability of NO and reducing oxidative stress and apoptosis of EPCs. Blockade of the renin-angiotensin system with angiotensinconverting enzyme inhibitors or angiotensin receptor blockers has also been shown to increase EPC number in patients with DM, 84,85 possibly mediated by their anti-inflammatory and antioxidative actions through the suppression of angiotensin II.…”

Stem cells of the adult cornea: From cytometric markers to therapeutic applications

“…During mitosis, stem cells renew themselves, e.g., at least one of the daughter cells preserves its ''stemness''. However, stem cells can exhibit an impressive proliferative capacity upon tissue injury or in culture (41)(42)(43)(44)(45)(46). The slow cycling of limbal stem cells allowed their detection as label retaining cells (13).…”

Stem cell therapies in the treatment of diabetic retinopathy and keratopathy

“…95 Further, some evidence suggests that diabetic EPC dysfunction can be improved or corrected by treatment with peroxisome proliferator-activated receptor (PPAR)-d and -g agonists GW501516, 103 rosiglitazone, 104 or atorvastatin. 105 Additionally, it was found that the levels of transforming growth factor (TGF)-b1 were significantly increased both in the EPCs (Figure 2) and in the serum of type 2 diabetic patients. 106 TGF-b1 inhibition in CD34þ cells increased cell survival, NO release, and in vivo vascular reparative ability (Figure 2), suggesting that this approach could be used for improving the vasoreparative potential of dysfunctional diabetic CD34þ cells for autologous therapy.…”