Angiotensin II stimulates synthesis of vascular smooth muscle cell proteoglycans with enhanced low density lipoprotein binding properties.
One mechanism by which Angiotensin II (AII) may promote atherogenesis is through modulation of proteoglycan (PG) metabolism by vascular smooth muscle cells (SMC). To test this hypothesis, we investigated the effect of AII on PG synthesis by human aortic SMC and the ability of the newly synthesized PG to bind low density lipoprotein (LDL). AII stimulated PG synthesis by SMC in a dose- and time-dependent manner. In the presence of 1 microM AII, medium and cellular PG increased by 73 and 97%, respectively. AII caused a 55% increase in biglycan mRNA which resulted in a 52% increase in biglycan synthesis. Losartan, an AII receptor antagonist, and broad and isoform-specific protein kinase C (PKC) inhibitors abolished the AII-induced up-regulation of PG synthesis. Moreover, direct activation of PKC with phorbol ester stimulated PG synthesis significantly. Similarly, inhibitors of tyrosine kinase also caused inhibition of PG synthesis. AII increased the size and charge density of the newly synthesized PG. In addition, AII stimulated the synthesis of PG that bound LDL with very high affinity by 2.5-fold to 3-fold over control. These results suggest that the AII-mediated alterations in vascular SMC PG metabolism may contribute to the pathophysiology of atherosclerosis.
Figueroa
Julio E
JE
Department of Medicine, Section of Infectious Diseases, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Vijayagopal
Parakat
P
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D001013:Aorta, Thoracic; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D002846:Chromatography, Affinity; D015180:Electrophoresis, Gel, Two-Dimensional; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011509:Proteoglycans / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1; D015398:Signal Transduction / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D011509:Proteoglycans; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D011505:Protein-Tyrosine Kinases; D019808:Losartan