Exogenous nitric oxide causes overexpression of TGF-beta1 and overproduction of extracellular matrix in human coronary smooth muscle cells.
OBJECTIVE
Nitric oxide (NO) is a major signalling molecule in the vascular system enhancing vascular smooth muscle cell relaxation and vasodilation. NO donors are the most frequently and repeatedly used drugs for relief from angina pectoris.


METHODS
We investigated the effects of the synthetic NO donor DETA/NO on cultured human coronary smooth muscle cells.


RESULTS
Cells exposed to 100 microM DETA/NO for 48-72 h were channeled into a cell cycle-arrested hypertrophic growth status associated with overexpression of TGF-beta(1) on both the protein and mRNA levels. Increased TGF-beta(1) transcription and translation were associated with enhanced synthesis of extracellular matrix components including the collagen types I and III as shown by immunocytochemistry and enhanced incorporation of [3H]proline. Higher incorporation of [35S]sulfate into chondroitin/dermatan sulfate and heparan sulfate containing proteoglycans was observed in DETA/NO treated cells than in controls. The ratio of chondroitin/dermatan sulfate to heparan sulfate did not change significantly.


CONCLUSIONS
Our results suggest a dual function of the overexpressed TGF-beta(1). Overexpressed TGF-beta(1) could stabilize the fibrous cap overlaying atherosclerotic plaques due to the accumulation of extracellular matrix components. However, the findings could also support a proatherogenic role of TGF-beta(1) resulting from the overexpression of LDL-binding proteoglycans.
Schmidt
Annette
A
Institute of Arteriosclerosis Research, University of Muenster, Department of Molecular Cardiology, Domagkstrasse 3, D-48149 Muenster, Germany.annschm@uni-muenster.de
Geigenmueller
Sven
S
Voelker
Wolfgang
W
Seiler
Petra
P
Buddecke
Eckhart
E
D002478:Cells, Cultured; D003331:Coronary Vessels; D003671:DEET / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*
D020030:Nitric Oxide Donors; D016212:Transforming Growth Factor beta; D003671:DEET; D009569:Nitric Oxide