Matrix metalloproteinase-2 cleavage of adrenomedullin produces a vasoconstrictor out of a vasodilator.
MMPs (matrix metalloproteinases) play a major role in the pathogenesis of hypertension by altering the extracellular matrix during cardiovascular remodelling. In the present study we show that MMP-2, but not MMP-9, cleaves the vasodilator peptide AM (adrenomedullin). Addition of the AM-binding protein, complement factor H, prevents this cleavage, providing a hitherto unknown mechanism of action for this binding protein. We identified the signature cleavage fragments and found some of them in human urine, suggesting that MMP-2 processing of AM may occur in vivo. Synthetic AM fragments regulated blood pressure in rats. The larger peptides are vasodilators, as is intact AM, whereas intermediate fragments did not affect blood pressure. In contrast, AM(11-22) elicited vasoconstriction. Studies of AM receptor activation in Rat2 cells confirm that the larger AM cleavage peptides activated this receptor, whereas AM(11-22) did not. The present study defines a new mechanism through which MMP-2 may regulate blood pressure by simultaneously eliminating a vasodilator and generating a vasoconstrictor.
Cell and Cancer Biology Branch and Vascular Biology Faculty, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. martinea@mail.nih.gov
Alfredo
A
Martínez
Hae-Ryong
HR
Oh
Edward J
EJ
Unsworth
Claudia
C
Bregonzio
Juan M
JM
Saavedra
William G
WG
Stetler-Stevenson
Frank
F
Cuttitta
D053607:Adrenomedullin; D000818:Animals; D001794:Blood Pressure; D002460:Cell Line; D005591:Chemical Fractionation / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D000242:Cyclic AMP / Q000378:metabolism; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007022:Hypotension / Q000188:drug therapy; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D051381:Rats; D011917:Rats, Inbred Lew; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide / Q000378:metabolism; D013379:Substrate Specificity; D014556:Urine / Q000737:chemistry; D014662:Vasoconstrictor Agents / Q000378:metabolism*; D014665:Vasodilator Agents / Q000378:metabolism*
D010446:Peptide Fragments; D010455:Peptides; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D053607:Adrenomedullin; D000242:Cyclic AMP; D020778:Matrix Metalloproteinase 2