Transforming growth factor-beta(1) stimulates L-arginine transport and metabolism in vascular smooth muscle cells: role in polyamine and collagen synthesis.
BACKGROUND
Transforming growth factor-beta(1) (TGF-beta(1)) contributes to arterial remodeling by stimulating vascular smooth muscle cell (VSMC) growth and collagen synthesis at sites of vascular injury. Because L-arginine is metabolized to growth-stimulatory polyamines and to the essential collagen precursor L-proline, we examined whether TGF-beta(1) regulates the transcellular transport and metabolism of L-arginine by VSMCs.


RESULTS
TGF-beta(1) increased L-arginine uptake, and this was associated with a selective increase in cationic amino acid transporter-1 (CAT-1) mRNA. In addition, TGF-beta(1) stimulated L-arginine metabolism by inducing arginase I mRNA and arginase activity. TGF-beta(1) also stimulated L-ornithine catabolism by elevating ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT) activity. TGF-beta(1) markedly increased the capacity of VSMCs to generate the polyamine putrescine and L-proline from extracellular L-arginine. The TGF-beta(1)-mediated increase in putrescine and L-proline production was reversed by methyl-L-arginine, a competitive inhibitor of cationic amino acid transport, or by hydroxy-L-arginine, an arginase inhibitor. Furthermore, the formation of putrescine was inhibited by the ODC inhibitor alpha-difluoromethylornithine, and L-proline generation was blocked by the OAT inhibitor L-canaline. L-Canaline also inhibited TGF-beta(1)-stimulated type I collagen synthesis.


CONCLUSIONS
These results demonstrate that TGF-beta(1) stimulates polyamine and L-proline synthesis by inducing the genes that regulate the transport and metabolism of L-arginine. In addition, they show that TGF-beta(1)-stimulated collagen production is dependent on L-proline formation. The ability of TGF-beta(1) to upregulate L-arginine transport and direct its metabolism to polyamines and L-proline may contribute to arterial remodeling at sites of vascular damage.
Durante
W
W
Houston VA Medical Center and the Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. wdurante@bcm.tmc.edu
Liao
L
L
Reyna
S V
SV
Peyton
K J
KJ
Schafer
A I
AI
D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D051381:Rats; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D011073:Polyamines; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001120:Arginine; D011392:Proline