Abstract
The matrix metalloproteinases gelatinase A (MMP-2) and gelatinase B (MMP-9) are implicated in the physiological and pathological breakdown of several extracellular matrix proteins. In the present study, we show that long-chain fatty acids (e.g. oleic acid, elaidic acid, and cis- and trans-parinaric acids) inhibit gelatinase A as well as gelatinase B with K(i) values in the micromolar range but had only weak inhibitory effect on collagenase-1 (MMP-1), as assessed using synthetic or natural substrates. The inhibition of gelatinases depended on fatty acid chain length (with C18 > C16, C14, and C10), and the presence of unsaturations increased their inhibitory capacity on both types of gelatinase. Ex vivo experiments on human skin tissue sections have shown that micromolar concentrations of a long-chain unsaturated fatty acid (elaidic acid) protect collagen and elastin fibers against degradation by gelatinases A and B, respectively. In order to understand why gelatinases are more susceptible than collagenase-1 to inhibition by long-chain fatty acids, the possible role of the fibronectin-like domain (a domain unique to gelatinases) in binding inhibitory fatty acids was investigated. Affinity and kinetic studies with a recombinant fibronectin-like domain of gelatinase A and with a recombinant mutant of gelatinase A from which this domain had been deleted pointed to an interaction of long-chain fatty acids with the fibronectin-like domain of the protease. Surface plasmon resonance studies on the interaction of long-chain fatty acids with the three individual type II modules of the fibronectin-like domain of gelatinase A revealed that the first type II module is primarily responsible for binding these compounds.
Highlights
The matrix metalloproteinases gelatinase A (MMP-2) and gelatinase B (MMP-9) are implicated in the physiological and pathological breakdown of several extracellular matrix proteins
We recently reported that oleic acid inhibited in a dose-dependent manner the hydrolysis of the fluorogenic substrate Mca-L-Pro-Leu-Gly-Leu-Dpa-AlaArg-NH2 [23] by gelatinase A [24, 25]
We conclude that interaction between fibronectin type II (FN-II) domain and unsaturated fatty acids leads to gelatinase inhibition because of the following: (i) oleic acid displayed markedly weaker inhibitory capacity toward gelatinase A deleted in FN-II modules; (ii) fatty acids bound avidly to the first FN-II module; and (iii) this module totally prevented the oleic acid-mediated inhibition of full-length gelatinase A
Summary
10:0 14:0 c9–14:1 16:0 c9–16:1 18:0 c9–18:1 t9–18:1 c9, t11, t13, c15–18:4 All t9, 11, 13, 15–18:4. Capric Myristic Myristoleic Palmitic Palmitoleic Stearic Oleic Elaidic cis-Parinaric trans-Parinaric a NI, no or less than 10% of inhibition, at [I]o ϭ 40 M. and B with similar efficiency but only have low inhibitory capacity toward collagenase-1. We conclude that interaction between FN-II domain and unsaturated fatty acids leads to gelatinase inhibition because of the following: (i) oleic acid displayed markedly weaker inhibitory capacity toward gelatinase A deleted in FN-II modules; (ii) fatty acids bound avidly to the first FN-II module; and (iii) this module totally prevented the oleic acid-mediated inhibition of full-length gelatinase A. The physiological relevance of our findings was substantiated by ex vivo experiments on human skin tissue sections demonstrating that C18-unsaturated fatty acid efficiently impeded the collagenolytic and elastolytic activities of gelatinases A and B, respectively
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