Smooth Muscle Cell Elastase, Atherosclerosis, and Abdominal Aortic Aneurysms

Abstract

Smooth muscle cells (SMC) were obtained by outgrowth of human aortic explants from abdominal aortic aneurysm (AAA) patients, aortic occlusive disease (AOD) patients, and transplant donors (controls). Specimens were incubated with medium alone or medium with either elastin-derived peptides (EDP, 5 micrograms/mL) or low-density lipoproteins (LDL, 5 micrograms/mL). Elastase activity (ng/mg total protein) was assayed from 4-week-old cultures. Control aortas obtained from patients significantly younger secrete an increased amount of elastase at baseline compared with AOD and AAA patients (p less than 0.05). Elastin-derived peptides caused a significant increase in elastase secretion in all groups. The increase in elastase secretion in response to EDP in AAA patients was significantly higher compared with AOD or control. Low-density lipoprotein had no effect on SMC elastase secretion. These data suggest that (1) aortic SMCs secrete elastase in response to EDP, (2) SMC elastase is age dependent, and (3) AAA SMC secrete an abnormally high amount of elastase compared with AOD and control aortas in response to EDP. Like the neutrophil, the SMC is highly responsive to the degradation products of elastin and in AAA patients secrete significantly increased amounts of elastase in response to the breakdown products of atherosclerosis.

Production and localization of 92-kilodalton gelatinase in abdominal aortic aneurysms. An elastolytic metalloproteinase expressed by aneurysm-infiltrating macrophages.

“…Because aneurysmal change is characterized by a marked decrease in aortic elastin, much of this effort has focused on known elastin degrading enzymes, such as the serine protease human neutrophil elastase. Although some data support the hypothesis that serine elastases are involved in the pathophysiology of aneurysms (16,17), our results suggest that MM~s, and in particular 92-Kilodalton Gelatinase in Abdominal Aneurysms 321 I Figure 6. 92-kD gelatinase is localized to macrophages in AAA.…”

“…However, clinical and pathologic differences between patients with aneurysms and those with occlusive atherosclerosis have challenged these assumptions (1-3, 43, 44), and investigations of the pathobiology of AAA have begun to assess the role of aneurysm-related connective tissue degrading enzymes in this disease (7,(15)(16)(17)(18)(19)(20)(21)(22)(23). Because aneurysmal change is characterized by a marked decrease in aortic elastin, much of this effort has focused on known elastin degrading enzymes, such as the serine protease human neutrophil elastase.…”

“…Because elastin is normally a highly stable extracellular matrix protein ( 13,14), locally active elastolytic proteinases likely contribute to aneurysmal dilatation by progressive degradation of this structurally important aortic wall component ( 15,16). In this context, increased proteolytic activities have been described in AAA, including serine elastases ( 17), plasminogen activators (18), and matrix metalloproteinases (MMPs) (19)(20)(21)(22), some or all of which may be involved in aortic wall elastin degradation (23).…”

Neutrophil Elastase in Human Atherosclerotic Plaques

“…1 A broad spectrum of elastolytic enzymes exists, including metalloelastases and cysteine proteases such as the cathepsins. [2][3][4] We recently demonstrated that nonmyeloid cells found in atheroma express MMP-8, a collagenase previously associated with neutrophils.…”

Proteomic evidence for the plasticity of cultured vascular smooth muscle cells

“…There have been several reports studying vascular SMCs that were grown in different types of media ranging from regular media such as M199 (14,15), DMEM (16)(17)(18), or DMEM/F12 (19) supplemented with FBS, with or without the addition of the above mentioned growth factors, or commercially available media specially optimized for the growth of SMCs (20)(21)(22)(23). While the optimized media appear valuable in terms of being successful in establishing new primary cell lines and being able to passage longer, they are not cost-effective.…”