Thiazolidinediones inhibit proliferation of microvascular and macrovascular cells by a PPARgamma-independent mechanism.
OBJECTIVE
This study evaluated the hypothesis that peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, including thiazolidinediones (TZDs) and the rexinoid LG100268 (LG), directly affect human vascular cell function (proliferation, cell cycle, protein expression, lactate release) independently of (1) their PPARgamma-activating potential and (2) the cells' vascular origin.


METHODS
Human umbilical vein endothelial cells (HUVECs), human adult vein endothelial cells (HAVECs), human retinal endothelial cells (HRECs) and human retinal pericytes (HRPYCs) were incubated (48 h) with 2-50 micromol/l rosiglitazone (RSG), RWJ241947 (RWJ), pioglitazone (PIO), troglitazone (TRO), 15-deoxy-Delta(12,14)-prostaglandin J2 (PGJ2) and LG. Proliferation, cell cycle distribution, protein expression, peroxisome proliferator-activated receptor responsive element (PPRE) transcriptional activity and mitochondrial effects were determined by [3H]thymidine incorporation, FACS analyses, western blots, reporter assays and lactate release respectively.


RESULTS
In HUVECs, RSG, RWJ, PIO, TRO, PGJ2 and LG reduced (p<0.01) proliferation (due to a G0/G1 cell cycle arrest) by up to 23%, 36%, 38%, 86%, 99% and 93% respectively. The antiproliferative response was similar in HRPYCs and HAVECs, but was attenuated in HRECs. Whereas p21WAF-1/Cip1 and p27Kip were differently affected in HUVECs, all agents reduced (p<0.05) expression of cyclins (D3, A, E, B), cyclin-dependent kinase-2 and hyperphosphorylated retinoblastoma protein. The rank order of the antiproliferative effects of TZDs in HUVECs (RSG approximately PIO approximately RWJ<TRO) contrasted their PPRE transcriptional activities (TRO<PIO<RSG<RWJ), but correlated with cellular lactate release. Proliferation inhibition and lactate release were mimicked by rotenone (mitochondrial complex I inhibitor).


CONCLUSIONS
In conclusion, this study suggests that the antiproliferative action of the TZDs in vascular cells is independent of their PPARgamma-activating and associated insulin-sensitising potential, but could relate to mitochondrial mechanisms.
Artwohl
M
M
Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria.
Fürnsinn
C
C
Waldhäusl
W
W
Hölzenbein
T
T
Rainer
G
G
Freudenthaler
A
A
Roden
M
M
Baumgartner-Parzer
S M
SM
D000328:Adult; D002455:Cell Division / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology*; D020286:Pericytes / Q000166:cytology / Q000187:drug effects; D012160:Retina / Q000166:cytology / Q000187:drug effects; D012171:Retinal Vessels / Q000166:cytology / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D014471:Umbilical Veins
D047495:PPAR gamma; D045162:Thiazolidinediones
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