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December 1997 - Paper of the Month
Carmeliet P, Moons L, Lijnen R, et al. Urokinase-
generated plasmin activated matrix metalloproteinases
during aneurysm formation. Nature Genetics 1997 Dec;
4:439-44.
Abstract (abridged from authors):
The molecular mechanisms predisposing to aneurysm
formation remain undefined. Indirect evidence suggests
that MMP's and plasminogen activators are involved.
Plasmin has been proposed as a possible activator in
vitro. Analysis of the aorta in mice with a deficiency
of apoliprotein E, either singly or combined with a
deficiency of t-PA or of ui-PA, indicated that deficiency
of u-PA protected against media destruction and aneurysm
formation, probably by means of reduced plasmin-dependent
activation of pro-MMP's. This finding may have
implications for the design of therapeutic strategies to
prevent aortic wall destruction by controlling u-PA gene
expression.
Comment by mdt:
First, before making any critical comments, I should
hasten to express satisfaction that the possible role for
plasmin in aneurysm pathogenesis (as proposed by my
laboratory (Surgery 1994; 116:472-8) is supported by the
present study. Second, I believe that the present data
is IMHO the most important ever published in support of
the notion that atherosclerosis may play an important
role in initiating a process that leads to aneurysm
formation in an experimental animal. Now, some
additional comments...
The authors assert that the aorta dilated to 1.5x normal
diameter, which is one of the thresholds for
differentiating arteriomegaly from early aneurysm
formation; but it would have been helpful for the reader
to have had a statistical morphometric analysis of these
data, and/or some gross photographs of the lesions. A
previous report by Zhang et al (Science 1992; 258: 468)
on the ApoE knockout mouse does not mention aneurysm
formation, although mean cholesterols were elevated 5x
over normal.
I would suggest caution in the temptation to extrapolate
the findings to man, because in human kindreds with ApoE
deficiency, tuberoeruptive xanthomatosis and type III
hypercholesterolemia occur (primary citation quoted by
Zhang). These findings would be unusual in the typical
patient with aneurysms. Also, the ApoE-4 polymorphism
appears to be a marker for susceptibility to Alzheimer's
Disease, by mechanisms presumably unrelated to its role
in dyslipoproteinemias or atherosclerosis. Perhaps the
ApoE null mouse has other pathophysiologic processes
ongoing, in addition to its disturbance in lipid
metabolism.
The authors point out that the subendothelial
inflammatory process in these mice is quite intense. The
mouse aorta is so thin (just a few elastic lamellae), it
is certainly a possibility that the inflammation could
reach the adventitia by contiguity, where an autoimmune
reaction might be triggered against autoantigenic aorta-
specific proteins associated with the load-bearing
collagen.
I congratulate the authors on their very stimulating and
interesting observations.