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Note to the reader: I have figured out a way to quote
the authors' abstract from MedLine in full, so we will
try it that way for a change. Also, as I am tidying up
my end-of-year notes, I notice that there are three topics
with clusters of interesting papers: Genetics, Enzymes, and
Clinical & Intervention. We will celebrate Y2K by doing
one of these clusters for each of the next three months.
1. Cystatin C deficiency in human atherosclerosis and aortic
aneurysms
Shi GP, Sukhova GK, Grubb A, Ducharme A, Rhode LH, Lee RT,
Ridker PM, Libby P, Chapman HA
JOURNAL OF CLINICAL INVESTIGATION
104: (9) 1191-1197 NOV 1999
Abstract:
The pathogenesis of atherosclerosis and abdominal aortic aneurysm
involves breakdown of the elastic laminae. Elastolytic cysteine
proteases, including cathepsins S and K, are overexpressed at sites of
arterial elastin damage, but whether endogenous local inhibitors
counterbalance these proteases is unknown. We show here that, whereas
cystatin C is normally expressed in vascular wall smooth muscle cells
(SMCs), this cysteine protease inhibitor is severely reduced in both
atherosclerotic and aneurysmal aortic lesions. Furthermore, increased
abdominal aortic diameter among 122 patients screened by
ultrasonography correlated inversely with serum cystatin C levels. In
vitro, cytokine-stimulated vascular SMCs secrete cathepsins, whose
elastolytic activity could be blocked when cystatin C secretion was
induced by treatment with TGF-beta(1). The findings highlight a
potentially important role for imbalance between cysteine proteases
and cystatin C in arterial wall remodeling and establish that cystatin
C deficiency occurs in vascular disease.
Comment by mdt: I guess MMP's aren't the whole story after all.
2. Enhanced embryonic nonmuscle myosin heavy chain isoform and matrix
metalloproteinase expression in aortic abdominal aneurysm with rapid
progression
Kamijima T, Isobe M, Suzuki J, Fukui D, Arai M, Urayama H, Nishimaki
K, Sekiguchi M, Kawasaki S
CARDIOVASCULAR PATHOLOGY
8: (5) 291-295 SEP-OCT 1999
Abstract:
Abdominal aortic aneurysms (AAAs) are characterized by structural
deterioration of aortic wall leading to progressive dilatation. The
histopathological changes in AAAs are particularly evident within the
elastic media, which is normally comprised mainly of vascular smooth
muscle cells (SMCs). There are vascular myosin heavy chain (MHC)
isoforms; SM2 is specifically expressed in differentiated SMCs and
SMemb is a nonmuscle-type MHC abundantly expressed in SMCs of the
fetal aorta with an immature phenotype. Although AAA altered
expression of matrix metalloproteinases (MMPs) and their tissue
inhibitors (TIMPs), pathophysiological role of SMC phenotypic
modulation in the AAA progression remains uncertain. To determine
whether phenotypic modulation in vascular SMCs contributes to arterial
medial degeneration, we examined MHC expression in SMCs of AAA. Aortic
specimens were obtained from patients with slowly progressed AAA (n =
12) and rapidly progressed AAA (n = 5), and compared with normal
aortic tissue (n = 3). Immunohistochemical staining was performed for
detection of SMemb, SM2, MMP (types 2 and 9) and TIMP (types 1 and 2).
Faint SMemb and abundant SM2 were observed in normal aorta, while the
balance shifted to SMemb predominance in AAAs. Compared with slowly
progressed AAA tissue, rapidly expanded AAA tissue demonstrated marked
increases in SMemb expression with suppressed SM2. Predominant SMemb
expression indicates presence of phenotypic modulated SMCs and
enhanced MMP; while abundant TIMP was seen in mature SMCs expressing
SM2. SMemb expression is markedly increased in AAA with MMP
enhancement, and a significant imbalance between SMemb and SM2 results
in rapid progression of AAA. (C) 1999 by Elsevier Science Inc.
Comment by mdt: MMP/TIMP findings not unanticipated, but the modulation
SMC phenotype is fascinating. A few years ago, one of students showed that SMC's
express DR antigens (Kosierkiewicz TA, Capella JF, Yin NX, Tilson MD. Expression
of the major histocompatibility complex (MHC) Class II (DR) antigen by smooth
muscle cells of the media of abdominal aortic aneurysms. Surgical Forum, 1996);
but I would have never guessed that they modulate to a fetal phenotype.
In the following two papers, the Wash U (St. Louis) research group under
leadership of RW Thompson implicate two new MMP's in AAA.
3. Expression of collagenase-3 (MMP-13) in human abdominal aortic
aneurysms and vascular smooth muscle cells in culture
Mao DL, Lee JK, Van Vickle SJ, Thompson RW
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
261: (3) 904-910 AUG 11 1999
Document type: Article Language: English Cited References: 47
Times Cited: 0
Abstract:
Collagen degradation is important in the pathogenesis of abdominal
aortic aneurysms (AAA) but the enzymes responsible are undefined.
Collagenase-3 is a recently described matrix metalloproteinase
(MMP-13) with limited tissue distribution and a highly regulated
pattern of expression. Using reverse transcription-polymerase chain
reaction and Southern blots, amplification products corresponding to
MMP-13 were uniformly detected in samples of AAA and atherosclerotic
aorta (ATH), but not in normal aortic controls. By densitometric
analysis of blots normalized to beta-actin, the expression of MMP-13
was 1.8-fold higher in AAA compared to ATH (P < 0.05). Immunoreactive
MMP-13 was localized to medial smooth muscle cells (SMC) in AAA tissue
and to human vascular SMC in culture, which also expressed MMP-13
mRNA. These findings indicate for the first time that SMC production
of MMP-13 may contribute to the pathophysiologic progression of AAA.
(C) 1999 Academic Press.
4. Expression and localization of macrophage elastase (matrix
metalloproteinase-12) in abdominal aortic aneurysms
Curci JA, Liao SX, Huffman MD, Shapiro SD, Thompson RW
JOURNAL OF CLINICAL INVESTIGATION
102: (11) 1900-1910 DEC 1 1998
Abstract:
Elastolytic matrix metalloproteinases (MMPs) have been implicated in
the pathogenesis of abdominal aortic aneurysms (AAA), a disorder
characterized by chronic aortic wall inflammation and destruction of
medial elastin. The purpose of this study was to determine if human
macrophage elastase (HME; MMP-12) might participate in this disease.
By reverse transcription-polymerase chain reaction, HME mRNA was
consistently demonstrated in AAA and atherosclerotic occlusive disease
(AOD) tissues(six of six), but in only one of six normal aortas.
Immunoreactive proteins corresponding to proHME and two products of
extracellular processing were present in seven of seven AAA tissue
extracts. Total HME recovered from AAA tissue was sevenfold greater
than normal aorta (P < 0.001), and the extracted enzyme exhibited
activity in vitro. Production of HME was demonstrated in the media of
AAA tissues by in situ hybridization and immunohistochemistry, but HME
was not detected within the media of normal or AOD specimens.
Importantly, immunoreactive HME was specifically localized to residual
elastin fragments within the media of AAA tissue, particularly areas
adjacent to nondilated normal aorta. In vitro, the fraction of MMP-12
sequestered by insoluble elastin was two- to fivefold greater than
other elastases found in AAA tissue. Therefore, HME is prominently
expressed by aneurysm-infiltrating macrophages within the degenerating
aortic media of AAA, where it is also bound to residual elastic fiber
fragments. Because elastin represents a critical component of aortic
wall structure and a matrix substrate for metalloelastases, HME may
have a direct and singular role in the pathogenesis of aortic
aneurysms.