Differential inhibitory effects of antidiabetic drugs on arterial smooth muscle cell proliferation

Abstract

We compared three drugs representing different classes of antidiabetic pharmacology (glyburide, a sulfonylurea; pioglitazone, a thiazolidinedione; and metformin, a biguanide) in terms of their direct effects on proliferation of cultured arterial smooth muscle cells (SMC). Rat aortic SMC were seeded at 4 x 10(4)/35 mm well. After 24 h, they were treated every 2 to 4 days for 2 weeks with 5% fetal bovine serum (FBS) in normal culture medium containing either drug vehicles or a low and a high but nontoxic level of glyburide (0.5 and 2.5 mumol/L), pioglitazone (1 and 5 mumol/L), and metformin (20 and 100 mumol/L). Vehicle-treated cells increased from 2 +/- 0 to 6 +/- 1 to 42 +/- 3 to 210 +/- 14 (cells per well x 10(4); 5 wells each) from day zero to 4 to 9 to 14. From day 9 to 14 these cell numbers were decreased an average of 20% by the 2.5 mumol/L glyburide (P < .05) and 43% by the 5 mumol/L pioglitazone (P < .05). The low levels of glyburide and pioglitazone and both the low and high levels of metformin failed to influence cell numbers. In a second experiment, even half the abovementioned high level of pioglitazone (2.5 mumol/L) still exerted a markedly greater antiproliferative effect on aortic SMC than a high level of 2.0 mumol/L glyburide (P < .05). In addition, neither drug's antiproliferative effect was influenced by a high level of insulin added to the medium (10 mU/mL). Similarly, a small but significant stimulatory effect of this high insulin on cell proliferation (P < .05) was not significantly affected by these two drugs (although pioglitazone tended to inhibit it). These results suggest that thiazolidinediones may be more useful antidiabetic agents than sulfonylureas and biguanides in inhibiting abnormal arterial SMC proliferation associated with atherosclerosis and postangioplastic restenosis which are common in diabetic patients.

Cardioprotection with pioglitazone is abolished by nitric oxide synthase inhibitor in ischemic rabbit hearts–comparison of the effects of pioglitazone and metformin

“…The mechanisms of action of pioglitazone remain poorly understood. However, it has been shown that pioglitazone has vasculo-protective effects [4][5][6][7][8][9] and probably enhances NO [10,11]. Metformin also possesses insulinsensitizing action [12].…”

Pioglitazone Inhibits In-Stent Restenosis in Atherosclerotic Rabbits by Targeting Transforming Growth Factor-β and MCP-1

“…Based on the literature, direct influence of PPAR-␥ agonist on SMCs is debatable as some studies report profound anti-proliferative and anti-migratory effects of pioglitazone on human and rat vascular SMCs, [31][32][33] whereas others suggest an absence of response. 34 The discrepancy may remain in the fact that thiazolidinediones may exert anti-proliferative effects independent of PPAR-␥, 35 specifically at higher concentrations.…”

Thiazolidinediones and Risk of Repeat Target Vessel Revascularization Following Percutaneous Coronary Intervention

“…In addition, this study duration was 1 year, while all but one of the prospective analyses continued for only 6 months. Repeat TVR rates after 6 months may substantially differ, though the majority of restenosis typically occurs early after stent placement (29,30).…”