Matrix Metalloproteinases (MMPs) are a family of at least 25 enzymes known to degrade the components of extracellular matrix. Both expression and activity of the enzymes are significantly increased during hypertension leading to myocardial remodeling. Previous studies showed that Angiotensin II (AngII) induces the release of MMPs; the use of clinically available Angiotensin-Converting Enzyme (ACE) inhibitors or broad spectrum MMP inhibitors in hypertensive animal models is associated with decreased MMP activity and improved hemodynamic function of the heart. Dipeptide Isoleucine-Tryptophan (IW), extracted from whey products, is a dipeptide with significant ACE inhibitory activity (IC₅₀= 0.7 mM). We tested whether the dipeptide exerts an indirect inhibitory effect on MMP2 and MMP9, the most important MMPs responsible for myocardial remodeling.

Methods: 

Effects of IW were studied both in vitro and in vivo. Human umbilical vein endothelial cells (HUVECs) were treated with Ang I and Ang II, and cotreated with IW and Captopril (CA) as a control. In addition spontaneously hypertensive rats (SHR) received different supplements in their food pellets: IW, CA or none (control). The inhibitory effects on MMPs were assessed using gelatin zymography.

Results: 

Both CA and IW inhibited conversion of Ang I to Ang II via inhibition of ACE activity in HUVECs and inhibited MMP2 (CA 96%±2%, IW 93%±3%) release (IC₅₀=5mM). CA and IW did not inhibit Ang II. In addition MMP activities were significantly decreased in myocardium of rats treated with IW and CA for 14 weeks.

Conclusion: 

IW is a potent ACE inhibitor. In addition IW is a potent MMP inhibitor acting via decreased ACE activity. The effect may be involved in myocardial remodeling during ACE-inhibition in the treatment of hypertension.