Human Aortic Wall Research Articles

Optimal proportions of gelatin–resorcin–formalin components in aortic surgery☆☆☆

Gelatin-resorcin-formalin (GRF) glue, a haemostatic agent often employed for aortic surgery, has beneficial effects on early results in surgery for acute aortic dissection but may have late adverse effects, probably due to excess use of the activators such as formaldehyde and glutaraldehyde. The purpose of this study was to determine the optimal proportions of GRF components that minimise toxicity to human aortic smooth muscle cells and elastin with acceptable adhesive strength. (1) The degree of polymerisation was examined at various proportions (activator/gelatin+resorcinol=0%, 2%, 4%, 6%, 8% and 10%) to estimate adhesive strength. (2) (i) The toxicity of the activator was confirmed 24h after its supplementation to human aortic smooth muscle cells in various proportions (activator/human aortic smooth muscle cell=0%, 0.5%, 1%, 1.5%, 2% and 2.5%). (ii) The toxicity of GRF glue to human aortic smooth muscle cells was evaluated 1h and 60 h after its supplementation (activator/gelatin+resorcinol=0%, 2%, 4%, 6%, 8% and 10%). Another set of experiments in the same study was also performed. The only difference was that GRF glues were washed after polymerisation to exclude non-polymerised constituents. (3) Effects of 8%-GRF glue on toxicity to elastin derived from human aortic wall cells were investigated using an immunoblotting method. (1) The polymerisation area increased dose dependently and that of the 10% activator/gelatin+resorcinol mixture was significantly wider than those of 6%, 4%, 2% and 0%, but had no significant difference from that of 8%. (2) (i) Human aortic smooth muscle cell death occurred in all dishes except activator-free dishes. (ii) Sixty hours after exposure to GRF glue, human aortic smooth muscle cell death occurred only in the 10% dish. In a washed GRF glue study, no human aortic smooth muscle cell death occurred in any dishes. (3) Toxicity to elastin was not significantly different between 8%-GRF glue and the control, whereas toxicity of elastase to elastin was significantly higher than for both the glue and the control. An 8%-GRF glue provides lower toxicity to human aortic smooth muscle cells and elastin with an acceptable degree of polymerisation, and thus seems to be an optimal proportion for GRF glue.

Short-term 20-mg atorvastatin therapy reduces key inflammatory factors including c-Jun N-terminal kinase and dendritic cells and matrix metalloproteinase expression in human abdominal aortic aneurysmal wall

Background Abdominal aortic aneurysm (AAA) accumulates features of a chronic inflammatory disorder and irreversible destruction of connective tissue. A recent experimental study identified c-Jun N terminal kinase (JNK) as a proximal signaling molecule in the pathogenesis of AAA and vascular dendritic cells as key players in the inflammatory reaction and degradation of the extracellular matrix. Statins can inhibit cell proliferation and vascular inflammation, which might help prevent AAA progression. However, supporting clinical data from human studies are lacking. We hypothesized that atorvastatin might inhibit JNK and dendritic cells, resulting in suppression of inflammatory cells and matrix metalloproteinases (MMPs) in human tissue of AAA. Methods Patients with AAA were randomized to atorvastatin (20 mg/day, n = 10) and non-treated ( n = 10) groups. After treatment for 4 weeks, patients underwent abdominal aorta replacement, tissue specimens were obtained, and tissue composition was assessed using immunohistochemistry with quantitative image analysis. Results Atorvastatin significantly reduced expression of JNK (1.1% vs. 8.1%, P = 0.0002) and dendritic cells (3.2 vs. 7.2, P = 0.003) compared to controls. T cells (142 vs. 315, P = 0.008), macrophages (13 vs. 24, P = 0.048) and immunoreactivity to MMP-2 (7.8% vs. 21%, P = 0.049) and MMP-9 (13% vs. 24%, P = 0.028) were also suppressed in the atorvastatin group. Serum low-density lipoprotein cholesterol level was decreased by 40% in the atorvastatin group. Conclusions Atorvastatin treatment acutely reduces JNK expression and dendritic cells, resulting in reduced inflammatory cell content and expression of MMPs in the AAA wall.

The role of dysfunctional HDL in atherosclerosis

This review focuses on HDL function in modulating LDL oxidation and LDL-induced inflammation. Dysfunctional HDL has been identified in animal models and humans with chronic inflammatory diseases including atherosclerosis. The loss of antiinflammatory function correlated with a loss of function in reverse cholesterol transport. In animal models and perhaps in humans, dysfunctional HDL can be improved by apoA-I mimetic peptides that bind oxidized lipids with high affinity.

Detection of infectious agents by polymerase chain reaction in human aortic wall

Several studies have been suggested that infectious agents may induce or progress the process of atherosclerosis in humans. In the present study, the samples of visually healthy human aortic wall were examined for the presence of Chlamydia pneumoniae, Mycoplasma pneumoniae, Helicobacter pylori, herpes simplex virus (HSV), and cytomegalovirus (CMV). Bacterial DNA of C. pneumoniae, M. pneumoniae, and H. pylori and viral DNA of HSV and CMV were analyzed by polymerase chain reaction. The specimens were obtained from 40 patients with atherosclerotic three-vessel stable coronary artery disease referred to surgical revascularization (coronary group) and 20 controls referred to aortic valve replacement (valve group). C. pneumoniae was detected in 11 of 40 samples of aorta in coronary group (27.5%) and 5 of 20 in valve group (25%). M. pneumoniae was found in 6 of 40 (15%) and 5 of 20 (25%) samples, and CMV was found in 22 of 40 (55%) and 10 of 20 (50%) samples. The most frequent detected pathogens were H. pylori and HSV. H. pylori was found in 32 of 40 samples of aortic wall in coronary group (80%) and 17 of 20 samples in valve group (85%), whereas HSV was found in 27 of 40 (67.5%) and 17 of 20 (85%) aortic wall specimens. Results demonstrate that C. pneumoniae, M. pneumoniae, H. pylori, CMV, and HSV can be detected in macroscopically healthy aortic wall of coronary and valve patients in similar frequency, which do not support hypothesis concerning the role of microorganisms in atherosclerosis etiology.

Abstract 1031: First Human Experiments: Aggressive Statin Therapy Reduced Key Inflammatory Factors including c-Jun N-terminal kinase (JNK) and Dendritic Cell and Matrix Metalloproteinase Expression in Human Abdominal Aortic Aneurysmal Wall

Abdominal aortic aneurysms (AAA) accumulate feature of a chronic inflammatory disorder and irreversible destruction connective tissue. Recent experimental study demonstrated that c-Jun N terminal kinase (JNK) was a proximal signaling molecule in the pathogenesis of AAA and vascular dendritic cells (DC) were the key molecular in inflammatory reaction and the degradation of the extracellular matrix. Statins can inhibit cell proliferation and vascular inflammation, which might contribute to prevent AAA progrssion. But supporting clinical data from human studies are lacking. We hypothesized that atorvastatin might inhibit JNK and DC, resulting in suppression of inflammatory cells and matrix metalloproteinase (MMPs) in human tissue of AAA. Methods : Patients with AAA were randomized to the atorvastatin (20 mg/day, 10 patients) group or control (10 patients) group. After treatment of 4 weeks, patients underwent abdominal aorta replacement, tissue specimens were obtained, and the tissue composition was assessed with special stains and immunocytochemistry with quantitative image analysis. Results :Atorvastatin significantly reduced JNK and DC expression (46% and 72%) compared to control. T cells, macrophages (60%, 72%, P< 0.05), and MMP-2 and MMP-9 immunoreactivity (47%, 43%, P< 0.05) were also suppressed in atorvastatin group. However, tissue expression of metalloproteinase 1 (TIMP-1) immunoreactivity and a collagen content by sirius red staining were similar in both groups. In atorvastatin group, serum LDL-C level was significantly decreased by 40%. Conclusion: Atorvastatin treatment reduced the JNK expression and DE, resulting in inflammatory cells content and the expression of MMPs in human abdominal aortic aneurysm wall.

Introduction to the Sixth International Workshop on Structure and Function of the Vascular System

Introduction to the Sixth International Workshop on Structure and Function of the Vascular System

Proinflammatory Profile Within the Grossly Normal Aged Human Aortic Wall

Studies in animal models demonstrate that angiotensin II and its downstream signaling molecules, that is, matrix metalloproteinases and monocyte chemoattractant protein-1, increase within the diffusely thickened intima of central arteries with aging. Whether such age-related changes occur within the human arterial wall is unknown. We harvested "grossly normal thoracic aortas" from 5 young (20+/-3 years) and 5 old white males (65+/-6 years) at necropsy, after death from traumatic causes. The intimae of older samples were markedly and diffusely thickened compared with younger intimae and contained increased levels of angiotensin-converting enzyme, angiotensin II, angiotensin II receptor type 1, matrix metalloproteinases 2/9, monocyte chemoattractant protein-1, and collagen I and III proteins. In situ activities of metalloproteinases 2/9 were also significantly enhanced within old, normal aortas. The thickened intima of older aortas also contained a 5-fold increase in the embryonic form of smooth muscle myosin heavy chain-labeled cells than that of younger aortas, and these fetal-type cells were colocalized with angiotensin II protein staining. The ability of isolated smooth muscle cells to invade an artificial basement membrane in response to a monocyte chemoattractant protein-1 gradient increased with age. Furthermore, angiotensin II increased the invasive capacity of young smooth muscle cells, and this effect was reduced by a metalloproteinase inhibitor or an angiotensin II receptor blocker. Thus, in the absence of lipid infiltration, the aged human aortic wall exhibits a proinflammatory profile that renders it a fertile substrate for the development of arterial disease, for example, atherosclerosis and hypertension.

Expression of secretory phospholipase A2s in human atherosclerosis development

Secretory phospholipase A2s (sPLA2s) contribute to the hydrolysis of phospholipid. Among them, sPLA2-IIA, -V, and -X have been regarded as enhancers of lipid accumulation in arterial intima. However, the distribution and production of the other types of sPLA2 in human aortic wall remain unclear. Therefore, in this study, the distribution and production of seven types of sPLA2 including IIA, IID, IIE, IIF, III, V, and X in atherosclerosis development in the human aorta were comprehensively examined by immunohistochemistry and in situ hybridization (ISH). The extent of sPLA2s expression increased with atherosclerosis development, but only sPLA2-IIF was never observed in the normal aorta. Double-immunostaining demonstrated that sPLA2-V expression was limited to smooth muscle cells (SMCs), although the other sPLA2s were expressed in both macrophages and SMCs. ISH using sPLA2 cDNAs revealed that the expression pattern of each mRNA was consistent with the results of immunohistochemistry for each corresponding sPLA2. These results indicate that the seven types of sPLA2 are expressed with various patterns in all stages of atherosclerosis development and may play an atherogenic role through degradation of phospholipid.

Circulatory support with attenuated pulse pressure alters human aortic wall morphology

In biology “form follows function.” Hypertension causes the musculoelastic aortic wall to thicken. 1 The only situation characterized by chronic hypotension with diminished pulse pressure is in patients having long-term support with a left ventricular assist device (LVAD). In a sheep model of chronic nonpulsatile blood flow, the medial layer thinned with apoptosis of smooth muscle cells (SMCs) and fragmentation of elastic fibers. 2 We sought to determine the clinical implications of this finding for destination therapy patients with a rotary blood pump. Clinical Summary In 7 patients with end-stage heart failure, computed tomographic scans were taken before implantation of a Jarvik 2000 LVAD (Jarvik Heart, Inc, New York, NY) and then annually during survival. Preoperative and latest postoperative aortic diameters were compared. After 5 deaths at between 7 days and 34 months of support, we obtained multiple full-thickness sections of the descending thoracic aorta. At least two nonadjacent sections were processed for each patient. The samples were fixed and stained with hematoxylin and eosin (HE StatsDirect Ltd, Sale, Cheshire, United Kingdom) and presented as median SD. Analysis of variance was calculated using 2-way analysis of variance with Bonferroni comparison. None of the computed tomographic scans showed an increase in aortic diameter out to 6 years (Figure 1). The 7-day LVAD specimens were indistinguishable from controls, but distinct morphologic changes were evident in the 3-month samples. Medial thickness diminished during prolonged support (1.411 0.140 mm in controls vs 1.006 0.170 mm in LVAD patients; P .0001). Medial SMCs decreased in number (147 31 per field in controls vs 63 12 per field in LVAD patients; P .0001) (Figure 2). From the EVG-stained sections there was a concomitant decrease in the medial layer elastin content. The process of atrophy appeared to progress with time. Discussion These novel findings were predictable but have not previously been confirmed in humans. One study limitation is that the autopsy samples could not be compared with the same patients’ aorta obtained during LVAD implantation. However, we were initially unaware of the sheep findings from our Terumo ventricular assist device program. 2 It was this that triggered the human study. Matched controls were the alternative. Irrespective of this, the human changes closely parallel the laboratory findings. 3 Arteries remodel in response to pressure and flow to provide a constant level of shear stress. Remodeling follows a complex interaction between signaling pathways and altered gene expression for nitric oxide synthase, platelet-derived growth factor, and transforming growth factor 1. 4 Because the Jarvik 2000 LVAD is afterload sensitive, mean systemic arterial blood pressure (MAP)

Up-Regulated Expression of the CXCR2 Ligand KC/GRO-α in Atherosclerotic Lesions Plays a Central Role in Macrophage Accumulation and Lesion Progression

Macrophage-mediated inflammation is central to atherogenesis. We have determined previously that the CXC chemokine receptor CXCR2 is involved in advanced atherosclerosis. We sought to determine whether one of the ligands of CXCR2, KC/GRO-alpha, can also modulate atherogenesis. KC/GRO-alpha(-/-) mice were generated and mated with the atherosclerosis-prone LDLR(-/-) mice. There was a significant reduction in atherosclerosis in mice lacking KC/GRO-alpha; however, this reduction was only approximately half that seen previously in mice lacking CXCR2 in the leukocyte. To determine whether CXCR2 is involved in the early formation of atherosclerosis, leukocyte-specific CXCR2(-/-) chimeric mice on LDLR(-/-) background were generated. Early fatty streak lesion formation in these mice was not affected by leukocyte CXCR2 deficiency whereas lesions were less developed in mice lacking leukocyte CXCR2 when atherosclerosis was allowed to progress to the intermediate stage. Macrophages were relatively sparse in the lesions of leukocyte CXCR2(-/-) mice despite robust MCP-1 expression. These studies indicate that KC/GRO-alpha/CXCR2 does not play a critical role in recruitment of macrophages into early atherosclerotic lesions but both arterial KC/GRO-alpha and leukocyte-specific CXCR2 expression are central to macrophage accumulation in established fatty streak lesions.

Mechanical deterioration underlies malignant behavior of aneurysmal human ascending aorta

The human ascending aorta becomes markedly prone to rupture and dissection at a diameter of 6 cm. The mechanical substrate for this malignant behavior is unknown. This investigation applied engineering analysis to human ascending aortic aneurysms and compared their structural characteristics with those of normal aortas. We measured the mechanical characteristics of the aorta by direct epiaortic echocardiography at the time of surgery in 33 patients with ascending aortic aneurysm undergoing aortic replacement and in 20 control patients with normal aortas undergoing coronary artery bypass grafting. Six parameters were measured in all patients: aortic diameter in systole and diastole, aortic wall thickness in systole and diastole, and blood pressure in systole and diastole. These were used to calculate mechanical characteristics of the aorta from standard equations. Aortic distensibility reflects the elastic qualities of the aorta. Aortic wall stress reflects the disrupting force experienced within the aortic wall. Incremental elastic modulus indicates loss of elasticity reserve. Aortic distensibility falls to extremely low levels as aortic dimension rises toward 6 cm (3.02 mm Hg(-1) for small aortas versus 1.45 mm Hg(-1) for aortas larger than 5 cm, P < .05). Aortic wall stress rises to 157.8 kPa for the aneurysmal aorta, compared with 92.5 kPa for normal aortas. For 6-cm aortas at pressures of 200 mm Hg or more, wall stress rises to 857 kPa, nearly exceeding the known maximal tensile strength of human aneurysmal aortic wall. Incremental elastic modulus deteriorates (1.93 +/- 0.88 MPa vs 1.18 +/- 0.21 MPa, P < .05) in aneurysmal aortas relative to that in normal aortas. The mechanical properties of the aneurysmal aorta deteriorate dramatically as the aorta enlarges, reaching critical levels associated with rupture by a diameter of 6 cm. This mechanical deterioration provides an explanation in engineering terms for the malignant clinical behavior (rupture and dissection) of the aorta at these dimensions. This work adds to our fundamental understanding of the biology of aortic aneurysms and promises to permit future application of engineering measurements to supplement aneurysm size in clinical decision making in aneurysmal disease.

Up-Regulation and Coexpression of MIF and Matrix Metalloproteinases in Human Abdominal Aortic Aneurysms

Abdominal aortic aneurysm (AAA) is a localized dilatation of the arterial wall as a result of extensive breakdown of its structural proteins by matrix metalloproteinases (MMPs). AAA continuously expand and may eventually rupture, causing high mortality rates. The molecular processes underlying expansion and rupture of AAA are only poorly understood. In this study, evidence was sought for a direct involvement of macrophage migration inhibitory factor (MIF) in the pathogenesis of AAA through up-regulating MMPs, with particular reference to macrophages. To this end, expression and cellular localization of MIF were analyzed in human aortic wall samples of stable AAA and ruptured AAA, and compared with control aorta and atherosclerotic aorta (AS). MIF expression was up-regulated in stable AAA and further intensified in ruptured AAA. The increased aneurysmal MIF expression was paralleled by an enhanced expression of specific MMPs, viz. MMP-1, MMP-9, and MMP-12, and by a decrease of their inhibitors. Immunohistochemical analysis of AAA and AS showed MIF protein in endothelial cells, smooth muscle cells (SMCs), macrophages, and T cells. MMP-1 (in SMCs and macrophages) and MMP-9 (in macrophages) were colocalized with MIF at the cellular level in ruptured AAA. The up-regulation of aneurysmal MIF/MMP expression was associated with an increased content of cytotoxic T cells.

The extracellular matrix of the human aortic wall: Ultrastructural observations by FEG-SEM and by tapping-mode AFM

Fragments of human ascending aorta harvested during heart surgery were cryofractured and observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). Elastic fibers appear as irregular, undulated laminae of variable size and shape. Their surface shows an evident fibrous texture suggestive of a criss–crossed, delicate filamentous scaffold and is marked by a number of features such as ridges, holes and protruding ribs. At higher magnification, both SEM and AFM show the surface composed of a finely granular material, with a bead size of approximately 20 nm. However, the thickness of the metal coating in one case, and the tip convolution effect on the other, may equally result in an artifactual enlargement of the structures, so that the beads may be significantly smaller. The surfaces created by the fracture always appear smooth and compact and with this technique do not reveal significant detail. The collagen component is mostly represented by small, uniform fibrils gathered in flexuous bundles and following a wavy course not unlike that of the elastic laminae. An orthogonal lattice of small proteoglycans is readily evident even without a specific treatment. Occasionally, the fibrils appear encrusted or engulfed in a grainy matrix reminiscent of the elastic fiber surface. Fluid Tapping-Mode Atomic Force Microscopy simultaneously reveals the surface-bound proteoglycans and the inner architecture of the fibrils, composed of smaller subunits following a spiral course with a winding angle of approximately 17°.

Matrix metalloproteinase 2 is suppressed by trapidil, a CD40-CD40 ligand pathway inhibitor, in human abdominal aortic aneurysm wall.

The activation of inflammatory cells and the production of matrix metalloproteinases (MMPs) are important in the pathogenesis of abdominal aortic aneurysm (AAA). Previous studies have demonstrated that the antiplatelet agent trapidil has multiple actions, including suppression of MMP expression through the inhibition of the CD40-CD40 ligand (CD40-CD40L) pathway in cultured cells. A recent clinical study suggested that trapidil might have functions beyond its antiplatelet action. Methods and results In the present study, we performed immunohistochemical analysis and semiquantitative reverse transcription-polymerase chain reaction to evaluate the effect of trapidil on the production of MMPs in cultured aortic tissues from patients with infrarenal AAA (n = 9) and control patients with aortoiliac occlusive disease (n = 7). The tissue concentrations of both MMP-2 and MMP-9 were significantly higher in AAA walls than in control aortic walls. Both trapidil and an anti-CD154 (CD40L) antibody significantly suppressed the protein production and mRNA expression of MMP-2 but did not inhibit those of MMP-9 in organ cultures of AAA wall specimens. MMP-9 was produced by macrophages and a lot of neutrophils in AAA tissues, whereas MMP-2 was derived from macrophages. CD40 was expressed on macrophages but not on neutrophils, and this expression could explain the differential effect of trapidil on the production of MMP-2 and MMP-9. Trapidil, a CD40-CD40L pathway inhibitor, suppressed mRNA expression and protein production of MMP-2 in AAA tissues, suggesting a potential therapeutic approach for the prevention or treatment of AAA.

Shear stress-induced collagen XII expression is associated with atherogenesis

Fluid shear stress has been shown to modulate various endothelial functions. We selected a shear stress-specific clone, identified as collagen XII, from a bovine aortic endothelial cell (BAEC) cDNA library. We confirmed that shear stress induces collagen XII expression at both the mRNA and protein levels in cultured BAECs and human umbilical vein ECs (HUVECs) by stimulating transcription. When HUVECs were exposed to shear stress, they secreted collagen XII protein and it was deposited underneath them. Strong expression of collagen XII was found in the intima of human aortic wall lacking atherosclerotic lesions, whereas weak expression was seen in the intima of atherosclerotic plagues. Furthermore, the downstream portion of atherosclerotic plaques showed apparently weak collagen XII expression compared with the upstream portion. These results suggest that collagen XII expression induced by fluid shear stress may play a role in stabilizing the vascular structure and preventing the formation of atherosclerotic lesions.

Ingrowth of aorta vascular cells into basic fibroblast growth factor-impregnated vascular prosthesis material: a porcine and human in vitro study on blood vessel prosthesis healing.

One of the most life-threatening vascular diseases is rupture of an abdominal aneurysm. The conventional treatment is based on surgical reconstruction. An alternative treatment is endovascular aneurysm repair (EVAR). Despite many advantages, one of the problems of EVAR is endoleakage from deficient healing between the aortic neck and the fabric of the endograft. We hypothesize that better healing, achieved with induction of vascular cell ingrowth into the graft material, would lead to better graft healing. Both pig aorta and human normal and aneurysmal aortic wall were used for organ cultures. Various growth factors were evaluated for the potential to induce intimal hyperplasia (ie, platelet-derived growth factor, vascular endothelial growth factor, and basic fibroblast growth factor [bFGF]). After the most potent growth factor had been selected, a vascular prosthetic material (Dacron fabric) impregnated with collagen and heparin was incubated with this growth factor. Impregnated pieces of Dacron were fixated on top of the aortic organ cultures for study of ingrowth of the neointima formation into the graft material. bFGF was the most potent growth factor to induce neointima in aortic organ cultures. The pieces of impregnated Dacron had a release of 5 ng/24 h of bFGF for a period of at least 28 days. With fixation on top of the aortic organ cultures, the impregnated Dacron was capable of inducing neointima formation and ingrowth of the neointima into the graft material after 28 days. We showed that a Dacron prosthesis impregnated with collagen, heparin, and bFGF is capable of inducing graft healing in our in vitro model, the aortic organ cultures of pig and human aortas. These results suggest that the problem of endoleakage with EVAR may be solved with a perfect proximal healing between the aortic wall and the prosthesis.

A 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, cerivastatin, suppresses production of matrix metalloproteinase-9 in human abdominal aortic aneurysm wall

Aim: Abdominal aortic aneurysm (AAA) is a common vascular degenerative disease. AAA wall contains inflammatory cells that produce matrix metalloproteinases (MMPs) that probably contribute to elastolysis and remodeling of the aneurysm. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the expression of various molecules (including MMPs) independently of their cholesterol-lowering effect. The aims of this study are to investigate whether statins could modulate the biology of AAA wall and have a potential therapeutic value against AAAs. Methods: We performed immunohistochemical analysis, evaluated MMP-9 production in the aortic wall from patients with infrarenal AAA (n = 10) and control patients with aortoiliac occlusive disease (n = 8), and examined the effect of cerivastatin on MMP-9 production in the AAA wall with organ culture. Results: Neutrophils and macrophages were the cellular sources of MMP-9 in the AAA wall. The tissue concentrations of both total and active MMP-9 were significantly higher in tissues from AAA walls than in control aortic walls. Cerivastatin (0.001 to 0.1 μmol/L) significantly reduced the tissue levels of both total and active MMP-9 in a concentration-dependent manner ( P < .001), and the production of tissue inhibitor of MMP-1 was unaffected. Cerivastatin neither reduced the number of infiltrating neutrophils and macrophages nor enhanced apoptosis of those cells, as evaluated with terminal transferase-mediated deoxyurisine triphosphate nick end labeling. Conclusion: These results suggest that cerivastatin can directly modulate the biology of the AAA wall and suppress MMP-9 production in the AAA wall by inhibiting the activation of neutrophils and macrophages, indicating that statin therapy could be useful for the prevention or treatment of AAA. (J Vasc Surg 2002;36:158-63.)

Herpesvirus (HSV-1, EBV and CMV) infections in atherosclerotic compared with non-atherosclerotic aortic tissue.

The viral nucleic acid of herpes simplex virus type 1 (HSV-1), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) was studied by polymerase chain reaction (PCR), Southern blotting and in situ hybridization (ISH) in aortic tissues from 33 autopsies. In 23 cases involving persons who ranged from 23 weeks to 75 years of age at the time of death, the tissue was histologically non-atherosclerotic. Of these 23, aortic tissues tested positive for HSV-1 in 13%, for EBV in 13% and for CMV in 4%. In the other 10 cases involving persons who were 53-75 years old at death, atherosclerotic aortic tissue tested positive for HSV-1 in 80%, for EBV in 80% and for CMV in 40%. Neither double nor triple infections occurred in the non-atherosclerotic group, whereas six of 10 were positive for two viruses, and two of 10 were positive for three viruses in the atherosclerotic group. By in situ hybridization, the viruses were localized in cells morphologically consistent with endothelial cells and smooth muscle cells. We detected HSV-1, EBV and CMV DNA in cells in the upper portion of the non-atherosclerotic aortic wall, whereas viral DNA was detected more extensively in atherosclerotic lesions than in non-atherosclerotic tissue. We also are the first to show the existence of EBV DNA in the human aortic wall. In conclusion, we suggest that the high incidence and kinds of herpesviruses are related to the high incidence of atherosclerosis.

Morphological examination of changes in intact and atherosclerotic human aortic walls induced by laser irradiation.

We performed morphological examination of intact and atherosclerotic aortic regions after laser irradiation with various characteristics (wavelength and energy). Particular attention was given to the type of damages to the vascular wall around craters formed by the laser beam. Combined irradiation with UV and visible lights produced least pronounced damages to surrounding tissues in the aortic wall.

Expression of peroxisome proliferator-activated receptor subtypes in human atherosclerosis.

To clarify the involvement of peroxisome proliferator-activated receptors (PPARs) in atherosclerotic plaque formation, we investigated the expression patterns of mRNA and protein of PPARalpha and PPARgamma in human aorta. Atheromatous plaque, fatty streak, and diffuse intimal thickening (DIT) were separated macroscopically, and each sample was divided into halves. Half of them were used for analysis of mRNA expression with reverse transcription-polymerase chain reaction and the others were used for histologic analysis. Both PPARalpha and PPARgamma mRNA were detected in all atheromatous plaques, all fatty streaks, and in some DIT. However, expressions of PPARalpha and PPARgamma were obviously less frequently found in DIT than in atheromatous plaques, and the intensity of these expressions was stronger in the atheromatous plaques than in the DIT. Compared with PPARalpha, PPARgamma mRNA was expressed more frequently in atheromatous plaques. In atheromatous plaques, PPARgamma mRNA was expressed independently, whereas PPARalpha mRNA was coexpressed with PPARgamma. PPARgamma protein was obviously found in the nuclei of endothelial cells, macrophages, mononuclear cells, and smooth muscle cells in the aortic intima. These results suggest that expressions of PPARalpha and PPARgamma in human aortic wall are involved in atherogenesis from the early stages.