Abstract
With recent work revealing that MMPs (matrix metalloproteinases) cleave an increasingly large degradome of bioactive and signalling molecules, the dogma that MMPs are extracellular-matrix-remodelling proteases is under challenge. In this issue of the Biochemical Journal, Martínez et al. have reported that AM (adrenomedullin), a potent vasodilator predominantly expressed by blood vessel endothelial and smooth muscle cells, and microvasculature-rich tissues, is another new bioactive substrate for MMPs in vivo. Cleavage by MMP-2, but not MMP-9, generates a series of peptides; two of which retain receptor agonist and vasodilator activity, three are inactive and, excitingly, AM(11-22), a small product containing a canonical disulphide loop, is a vasoconstrictor. In view of the robust vasodilatory and other cardiac protective activities of AM in inhibiting myocardial fibrosis this represents a potent new systemic role for MMP-2 in the cardiovasculature. Hence, the paper by Martínez et al. directly implicates MMP activity in the development of hypertension and paradoxically in stimulating myocardial fibrosis, therefore pointing to exciting new possibilities for utilizing MMP-2-specific inhibitors as a new mode to treat blood pressure and heart disease.