MMP/MT-MMP nimistä, substraateista ja inhibiittoreista. Treenaus ja obsesitas aspekti!

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 Abstract: Matrix metalloproteinases (MMPs) are zinc- and calcium-dependent endoproteinases that have the ability to break down extracellular matrix. The large range of MMPs’ functions widens their spectrum of potential role as activators or inhibitors in tissue remodeling, cardiovascular diseases, and obesity.
 In particular, MMP-1, -2, and -9 may be associated with exercise and obesity. Thus, the current study reviewed the effects of different types of exercise (resistance and aerobic) on MMP-1, -2, and -9. Previous studies report that the response of MMP-2 and -9 to resistance exercise is dependent upon the length of exercise training, since long-term resistance exercise training increased both MMP-2 and -9, whereas acute bout of resistance exercise decreased these MMPs. Aerobic exercise produces an inconsistent result on MMPs, although some studies showed a decrease in MMP-1. Obesity is related to a relatively lower level of MMP-9, indicating that an exercise-induced increase in MMP-9 may positively influence obesity. A comprehensive understanding of the relationship between exercise, obesity, and MMPs does not exist yet. Future studies examining the acute and chronic responses of these MMPs using different subject models may provide a better understanding of the molecular mechanisms that are associated with exercise, obesity, and cardiovascular disease.

Keywords: cardiovascular disease, gelatinases, collagenases, TIMP

I nhibition of MMPs

Two types of MMP inhibitors exist: endogenous and exogenous inhibitors.

 Tissue inhibitors of metalloproteinase (TIMPs) are endogenous inhibitors that can be secreted (TIMP-1, TIMP-2, TIMP-4) or bound to ECM components (TIMP-3).²⁰ They inactivate MMPs by forming bonds with catalytic zinc in 1:1 ratios within the MMP structure.²¹ 

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 They do so by creating noncovalent interactions between the N-terminal domain of the TIMP and the active site of MMPs. Recent studies have shown TIMPs’ therapeutic potential in cardiovascular diseases (CVDs)

The MMP-inhibitory effects of TIMP-1 involve binding of C-terminal domain to pro-MMP-2 and pro-MMP-9. TIMP-1 may specifically help ECM manipulation in ischemia in such a way that it may be a surrogate marker for increased ECM turnover.²²

TIMP-2 reverses ECM remodeling in human cardiac tissue in a dose-dependent manner.²³

 TIMP-3 prevented degradation of cardiac tissue matrix after a myocardial infarction by reducing MMPs in vascular smooth muscle cells.²⁴

 Changes in the ECM of atrial fibroblast in rheumatic heart disease have been associated with TIMP-4 expression.²⁵

Exogenous inhibitors include hydroxamic acid derivative and thiirane gelatinase inhibitor SB-3CT on several MMPs.^26–29 Batimastat (BB-94), a hydroxamic acid derivative, has been recently found to treat aneurysms on using nanoparticle technology to directly administer anti-MMP target to abdominal aorta aneurysm.³⁰ In rat aorta cell culture, administration of BB-94 decreased 90% of MMP-9 activity and 10% of MMP-2 activity, while showing no effect on TIMP-2 activity.
The effect of change in MMP activity was tested by injecting BB-94 directly into the abdominal aorta. The blank control showed a 269% increase in the aneurysm, while the treatment group showed only a 40% increase in expansion.
Another derivative, mastmariat, has shown success as a therapeutic drug in repressing non-small-cell lung cancer (NSLC) in a Phase I trial.³¹ Oral administration of marimastat was added to the accepted treatment with carboplatin and paclitaxel in order to test whether or not marimastat would affect the kinetics of the treatment. TIMPs and hydroxamic acid derivatives play significant roles in general physiology and pathology, and thus can develop as a therapeutic target in the future.