Key result
Rosiglitazone inhibits Angiotensin II-induced atherosclerosis and fibrosis in rat VSMCs via the mTOR pathway.
Why the study?
The mechanism underlying the inhibition of vascular smooth muscle cell proliferation and fibrosis by thiazolidinediones like rosiglitazone needs elucidation.
Does rosiglitazone inhibit angiotensin II-induced proliferation and fibrosis in rat aortic vascular smooth muscle cells?
Does rosiglitazone inhibit angiotensin II-induced proliferation and fibrosis in rat aortic vascular smooth muscle cells?
Rosiglitazone directly inhibits the pro-atherosclerotic and pro-fibrotic effects of Angiotensin II on vascular smooth muscle cells, mediated in part through the mTOR pathway.
Hypothesis-generating for rosiglitazone in vascular remodeling; clinical relevance in human atherosclerosis or fibrosis remains untested.
VSMC (vascular smooth muscle cell) proliferation contributes significantly to intimal thickening in atherosclerosis, restenosis and venous bypass graft diseases. Ang II (angiotensin II) has been implicated in VSMC proliferation though the activation of multiple growth-promoting signals. Although TZDs (thiazolidinediones) can inhibit VSMC proliferation and reduce Ang II-induced fibrosis, the mechanism underlying the inhibition of VSMC proliferation and fibrosis needs elucidation. We have used primary cultured rat aortic VSMCs and specific antibodies to investigate the inhibitory mechanism of rosiglitazone on Ang II-induced VSMC proliferation. Rosiglitazone treatment significantly inhibited Ang II-induced rat aortic VSMC proliferation in a dose-dependent manner. Western blot analysis showed that rosiglitazone significantly lowered phosphorylated ERK1/2 (extracellular-signal-regulated kinase 1/2), Akt (also known as protein kinase B), mTOR (mammalian target of rapamycin), p70S6K (70 kDa S6 kinase) and 4EBP1 (eukaryotic initiation factor 4E-binding protein) levels in Ang II-treated VSMCs. In addition, PPAR-γ (peroxisome-proliferator-activated receptor γ) mRNA increased significantly and CTGF (connective tissue growth factor), Fn (fibronectin) and Col III (collagen III) levels decreased significantly. The results demonstrate that the rosiglitazone directly inhibits the pro-atherosclerotic effect of Ang II on rat aortic VSMCs. It also attenuates Ang II-induced ECM (extracellular matrix) molecules and CTGF production in rat aortic VSMCs, reducing fibrosis. Importantly, PPAR-γ activation mediates these effects, in part, through the mTOR-p70S6K and -4EBP1 system.
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Kim et al. (2011) studied Angiotensin II-induced vascular smooth muscle cell proliferation. Rosiglitazone vs. Angiotensin II alone was evaluated on VSMC proliferation and protein levels (ERK1/2, Akt, mTOR, p70S6K, 4EBP1, CTGF, Fn, Col III). Rosiglitazone directly inhibits the pro-atherosclerotic effect of Angiotensin II on rat aortic vascular smooth muscle cells and reduces fibrosis, mediated in part through the mTOR pathway.
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