**8. Possibilities of pharmacological modulation of metalloproteinases activity**

Patients with a high activity of MMPs within the aneurysm are at increased risk of its rupture leading to serious clinical consequences including death. It is of a great importance to find agents which can inhibit MMPs activity and reduce this risk.

Doxycycline, a tetracycline antibiotic, is a known inhibitor of metalloproteinases activity with a growing body of evidence of its beneficial effects observed in animal studies. However data from human studies comprising 6 controlled trials and 2 cohort studies gave conflicting results. The safety of long term use of doxycycline needs evaluation [24].

Statins are a well known group of drugs lowering plasma cholesterol level used to reduce the risk of a coronary heart disease. They have a pleiotropic mode of action reducing the progress of atherosclerosis. Experimental studies indicate that simvastatin can reduce the activity of MMP-2 and MMP-9 in AAA and suppress the development and expansion of abdominal aortic aneurysm. A study performed on samples derived from patients receiving atorvastatin and undergoing surgical treatment for AAA gave promising results demonstrating a significantly reduced activity of MMP-13. Another study with short term, 4 weeks, administration of atorvastatin preceding the operation did not show any differences in the activity of MMP-2, MMP-8, MMP-9, TIMP-1 or TIMP-2. These data indicate that statins may require a long term use to develop their beneficial influence on MMPs' activity [25-27].

Drugs which are administered for a long time focus the scientists' interest. Antihypertensive drugs have been studied in this aspect. Calcium channel blocker, azelnidipine, decreased the activity of MMP-2 and MMP-9. The similar influence of angiotensin II receptor blockers, olmesartan and losartan, was observed. The latter was also shown to act synergistically with doxycycline. Perindopril, an angiotensin converting enzyme inhibitor, is known as an anti-hypertensive agent with an ability to affect vascular wall remodeling. In an experimental study perindopril significantly reduced the activity of MMP-2 and MMP-9. In animal studies the activity of MMP-2 and MMP-9 were also decreased by edaravone, a scavenger of reactive oxygen species, resveratrol, a plant derived polyphenolic compound. Two inhibitors of cyclic adenosine monophosphate phosphodiesterase (PDE) were also shown to inhibit the activity of metalloproteinases. Cilostazol, the inhibitor of PDE-3 decreased the activity of MMP-2 and MMP-9, whereas ibudilast, which predominantly blocked PDE-4, decreased the expression of MMP-9 [28-37].

Although the experimental studies indicate that various drugs can reduce the expression and activity of metalloproteinases, their potential use in humans to protect from AAA or inhibit its development requires further studies. Their efficacy and safety of a long term administration must be proven.

#### **Author details**

70 Aneurysm

**activity** 

[25-27].

detect AAA at a high risk of rupture [22, 23].

expanding experimental AAA. This method allows the detection of MMP activity within the inflammatory infiltrate within AAA and may become a potential non-invasive method to

Patients with a high activity of MMPs within the aneurysm are at increased risk of its rupture leading to serious clinical consequences including death. It is of a great importance

Doxycycline, a tetracycline antibiotic, is a known inhibitor of metalloproteinases activity with a growing body of evidence of its beneficial effects observed in animal studies. However data from human studies comprising 6 controlled trials and 2 cohort studies gave

Statins are a well known group of drugs lowering plasma cholesterol level used to reduce the risk of a coronary heart disease. They have a pleiotropic mode of action reducing the progress of atherosclerosis. Experimental studies indicate that simvastatin can reduce the activity of MMP-2 and MMP-9 in AAA and suppress the development and expansion of abdominal aortic aneurysm. A study performed on samples derived from patients receiving atorvastatin and undergoing surgical treatment for AAA gave promising results demonstrating a significantly reduced activity of MMP-13. Another study with short term, 4 weeks, administration of atorvastatin preceding the operation did not show any differences in the activity of MMP-2, MMP-8, MMP-9, TIMP-1 or TIMP-2. These data indicate that statins may require a long term use to develop their beneficial influence on MMPs' activity

Drugs which are administered for a long time focus the scientists' interest. Antihypertensive drugs have been studied in this aspect. Calcium channel blocker, azelnidipine, decreased the activity of MMP-2 and MMP-9. The similar influence of angiotensin II receptor blockers, olmesartan and losartan, was observed. The latter was also shown to act synergistically with doxycycline. Perindopril, an angiotensin converting enzyme inhibitor, is known as an anti-hypertensive agent with an ability to affect vascular wall remodeling. In an experimental study perindopril significantly reduced the activity of MMP-2 and MMP-9. In animal studies the activity of MMP-2 and MMP-9 were also decreased by edaravone, a scavenger of reactive oxygen species, resveratrol, a plant derived polyphenolic compound. Two inhibitors of cyclic adenosine monophosphate phosphodiesterase (PDE) were also shown to inhibit the activity of metalloproteinases. Cilostazol, the inhibitor of PDE-3 decreased the activity of MMP-2 and MMP-9, whereas ibudilast, which predominantly

Although the experimental studies indicate that various drugs can reduce the expression and activity of metalloproteinases, their potential use in humans to protect from AAA or

conflicting results. The safety of long term use of doxycycline needs evaluation [24].

**8. Possibilities of pharmacological modulation of metalloproteinases** 

to find agents which can inhibit MMPs activity and reduce this risk.

blocked PDE-4, decreased the expression of MMP-9 [28-37].

Krzysztof Siemianowicz *Medical University of Silesia, Department of Biochemistry, Poland* 

#### **9. References**


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**Chapter 5** 
