Matrix Metalloproteinases: Contribution to Pathogenesis, Diagnosis, Surveillance and Treatment of Abdominal Aortic Aneurysms

Nikolaos P. Kadoglou; Christos D. Liapis

Disclosures

Curr Med Res Opin. 2004;20(4) 

In This Article

Pharmacological Inhibition of MMPs

Pharmacological treatment aiming at decelerating, even preventing expansion, of small asymptomatic aneurysms provides a novel treatment option. Most importantly, drug therapy with 60% effectiveness, good compliance and tolerability prolongs the interval between diagnosis and need for surgery for up to 5 years in patients with AAA sized less than 4 cm.[1] Considering that MMPs play a central role in matrix degradation and aneurysm progression, it seems that these proteinases constitute attractive targets of drug treatment.

Doxycycline, a synthetic tetracycline derivative with antibiotic and anti-MMPs properties, provides a potentially effective medical agent. Doxycycline nonselectively inhibits MMPs by binding to the active zinc site and secondarily to the inactive calcium ion site causing conformational changes and loss of enzymatic activity.[82] in vitro studies have shown that doxycycline significantly reduces MMP-9 activity and concomitant elastin degradation.[30,100] Besides its direct MMP antagonistic function, doxycycline suppresses the activation of proMMP-2 and inhibits the mononuclear phagocyte expression of MMP-9 mRNA.[101,102,103] However, Kaito et al.[82] reported that doxycycline does not affect MMP-2 production. On the other hand, inflammatory infiltration is not influenced by doxycycline. Histological examinations in doxycycline-treated animals have revealed that artificial aortic dilatation is remarkably repressed by preserving the medial elastin and reducing MMP-9 production and activity. Overall, doxycycline exerts its effects in a dose dependent manner down regulating MMPs within the aortic wall. The maintenance of elastic lamellae and the aortic wall stabilization restrict the incidence and severity of experimental aneurysms in animal models.[82,100,102,104] Plasma levels of doxycycline in mice, comparable with those achieved in humans, attenuate AAA growth rate by 33-66% promising that in clinical practice they could increase the percentage of patients who remain under surveillance and do not reach the endpoint of surgical repair.[105]

In all clinical studies doxycyline appears to be so far a convenient drug with low cost, well-recognised safety profile, clinical tolerability and without serious side effects.[101,106] Short-term treatment with doxycycline prior to elective operation diminishes MMP-9 mRNA and suppresses the extracellular post-translational processing of proMMP-2.[101] Prolonged administration of this tetracycline derivative in patients with small asymptomatic AAAs is considered to be of great interest. There is only one recent multicentre clinical study where long-term doxycycline treatment was associated with reduced plasma MMP-9 levels.[106] Therefore, longitudinal administration of doxycycline is expected to restrict matrix disruption in aneurysms. Besides this, there are indications from a small pilot study that doxycycline lowers the expansion rate and contributes to Chlamydia pneumoniae eradication.[107] However, it is doubtful whether the presence of the Chlamydia pneumoniae in the AAA is associated with increased MMPs activity and aneurysm development.[108] Thus, the favourable effects of doxycycline on aneurysm growth rate deserve further investigation.

Another attractive option of aneurysmal disease pharmacotherapy is to target the inflammatory response and so interrupt the MMPs pathway. Inflammatory cells in the adventitial and medial layers apart from elaborating MMPs, release pro-inflammatory (IL-1β, IL-6) cytokines that induce MMP expression in AAAs.[109] Non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, reduce cytokine release (IL-1β, IL-6) in aortic explants and prevent elastase-induced abdominal aortic aneurysms in rats.[110] In a case control study NSAIDs halved the rate of AAA expansion, suggesting a potentially effective treatment. In the aneurysm wall prostaglandin E2 (PGE2) synthesis by macrophages is enhanced. PGE2 regulates MMP-9 expression and has been proved to have detrimental effects on SMCs viability and cytokine secretion in vitro. There is evidence that indomethacin reduces PGE2 synthesis and consequently MMP-9 production.[111] NSAIDs may have favourable effects on the aneurysm wall by reducing both the inflammatory and proteolytic processes. These concepts require further confirmation.

In the past decade a number of substances have been proposed as alternative factors for the treatment of small asymptomatic AAAs. Several investigators have suggested that β-blocker therapy may slow the expansion rate of aneurysms by a still unknown mechanism. The results of their studies clearly show that β-adrenergic antagonists significantly attenuate the growth rate of large (> 5 cm) AAAs and also reduce the size of experimental AAAs in hypertensive rats.[112,113]

In consideration of the finding that endogenous MMPs play an essential role in aortic wall degeneration, several researchers have examined the effects of several synthetic MMP-inhibitors on experimental models of AAAs. Marimastat, a competitive inhibitor of MMP-2 may have toxic effects on VSMCs and so it reduces matrix degradation and contributes to medial elastin preservation.[114] Batimastat (BB-94) and RS132908, hydroxamate-based broad-spectrum MMP inhibitors, have been shown to suppress the expansion of experimental AAA in rat models.[115,116] Finally, the oral administration of RS-113456, a non-selective MMP inhibitor, diminishes the flow-mediated arterial enlargement in a rat arteriovenous fistula model.[117]

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG CoA), besides their cholesterol lowering effects, suppress the expression of various inflammatory molecules including MMPs.[118] The beneficial effects of these inhibitors are attributed not only to their actions on lipids, but also on numerous cardiovascular risk factors.[119] The addition of maximum clinical doses of cerivastatin in AAA tissue organ cultures down-regulates the production of MMP-9 and may prevent elastolysis in patients with AAA,[120] though it must be noted that cerivastatin was withdrawn from the market in 2001 for safety reasons. So it is hypothesized that several other members of the statins family may exhibit a similar effect and that future studies should examine the clinical validity of these hypolipidemic factors in the prevention of aneurysms.

The cumulative results of the above studies suggest that MMP inhibition is a feasible and promising alternative strategy for suppressing aortic degeneration. Further large, randomized clinical trials are required to confirm the importance of MMPs as potential therapeutic targets in patients with AAAs, particularly those with small asymptomatic aneurysms.

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