Rosiglitazone increases matrix production and quenches inflammation: studies in human cells.
BACKGROUND
Type 2 diabetes (T2D) is characterized by an accelerated atherogenesis, a process to which both proliferative and inflammatory responses contribute. Peroxisome proliferator-activated receptors-gamma (PPARgamma) agonists have both anti-proliferative and anti-inflammatory properties. We tested the effect of therapeutic doses of rosiglitazone on proliferative and inflammatory pathways in fibroblasts (HF) from five controls (C) and five T2D patients, and in aortic smooth muscle cells (hSMC).


METHODS
Transforming growth factor-beta (TGFbeta) and interleukin-6 (IL-6) expression, and IL-6, laminin and fibronectin release were measured. To identify the involved intracellular signalling, extracellular signal-regulated kinases (ERK)1/2 phosphorylation and p38 activation were evaluated.


RESULTS
Both phorbol 12-myristate 13-acetate (PMA) [a protein kinase C (PKC) activator] and rosiglitazone increased TGFbeta expression and fibronectin and laminin release in C and T2D patients. Rosiglitazone effect was reversed by its specific inhibitor Sr202. The combination PMA + rosiglitazone was additive in C, but not in T2D patients. IL-6 production was stimulated by PMA in both C and T2D patients; this effect was prevented by rosiglitazone in a Sr202-inhibitable manner. Experiments performed in hSMC yielded the same results. Rosiglitazone increased p38 activation more in C than in T2D patients; PMA-induced phosphorylation of ERK1/2 was similarly reduced in both cells.


CONCLUSIONS
In HF and hSMC, rosiglitazone stimulates the synthesis of matrix components via enhanced TGFbeta expression; when combined with PMA, the resulting PKC activation is mediated by enhanced p38 phosphorylation. On the other hand, rosiglitazone quenches inflammation in both cell types, by counteracting PMA-induced phosphorylation of ERK1/2.
Solini
Anna
A
Department of Internal Medicine, University of Pisa School of Medicine, Italy. a.solini@med.unipi.it
Santini
Eleonora
E
Madec
Stephanie
S
Nannipieri
Monica
M
Bonotti
Alessandra
A
Cuccato
Sabina
S
Ferrannini
Ele
E
D018929:Cell Culture Techniques; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005109:Extracellular Matrix / Q000187:drug effects / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000517:prevention & control*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000235:genetics
D005353:Fibronectins; D007004:Hypoglycemic Agents; D015850:Interleukin-6; D007797:Laminin; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D000077154:Rosiglitazone