The main cellular elements of atherosclerotic plaques are smooth muscle cells. Because these plaques differ from their precursors in the underlying artery wall in several ways, we have asked the question: Are human atherosclerotic plaques polyclonal or monoclonal in their origin? The X-linked glucose-6-phosphate dehydrogenase (EC 1.1.1.49) in heterozygotic females has been used to obtain an answer. 30 Plaques of different degrees of complexity and 59 samples of normal aorta and iliac artery walls from four females, 25-79 years old, were investigated. The data show that fibrous caps even of relatively large atheromatous plaques, 0.5 cm or greater in diameter, are composed of cells that produce solely or predominantly one enzyme type, whereas samples of artery wall media and intima as small as 0.1 mm(3) are regularly composed of a mixture of cell types. If plaques were a response to injury akin to a healing wound, a reaction to a growth stimulant, or formed due to an organization of a mural thrombus, they would be expected to be polyclonal. Hence, the results imply that atherosclerotic plaques in human beings arise by another mechanism. The mechanism compatible with the monoclonal nature of atherosclerotic plaques is mutation, and the likely causes are chemical mutagens or viruses.

elsewhere (35, 36).Probes and in Situ Hybridization. RNA probes were transcribed from pGEM-1 transcription plasmid (Promega) that contained a 110-bp sequence of mouse SAA1 cDNA (p125) (37). This nucleotide sequence encompasses a domain coding for amino residues 30-66 that is highly conserved among various species and is 81% homologous with human SAA1 and SAA2 mRNAs and is 71% homologous with human apoSAA4 mRNA (refs. 4 3186The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Despite the lack of direct evidence for cell multiplication, proliferation of smooth muscle cells in human atherosclerotic lesions has been assumed to play a central role in ontogeny of the plaque. We used antibodies to cell cyclerelated proteins on tissue sections of human arteries and coronary atherosclerotic plaques. Specific cell types were identified by immunochemical reagents for smooth muscle, monocyte-macrophages, and other blood cells. Low rates of smooth muscle cell proliferation were observed. Macrophages were also observed with rates of proliferation comparable to that of the smooth muscle. Additional replicating cells could not be dermed as belonging to specific cell types with the reagents used in this study. These rmdings imply that smooth muscle replication in advanced plaques is indolent and raise the possibility of a role for proliferating leukocytes.Haust (1) first demonstrated the prominence of smooth muscle cells in human atherosclerotic plaques. Since then, smooth muscle proliferation has been assumed to be a critical part of the pathogenesis of atherosclerosis (2-4). This concept was supported by the demonstration that human plaques are monoclonal (5,6), as was the idea that lesions originate by cell proliferation rather than by migration of polyclonal cells from the media (3, 4). Monoclonality, however, is indirect evidence for proliferation. While there is direct evidence for smooth muscle proliferation in animal models, direct, quantitative evidence of proliferation has not been obtained in human lesions. Moreover, the animal lesions appear to be polyclonal and could, therefore, arise by a different mechanism (7,8). The recent development of monoclonal antibodies to proliferation-associated antigens allowed us to measure directly proliferation in human tissues (9-11). We used a monoclonal antibody to the proliferating cell nuclear antigen (PCNA; also known as cyclin A PCNA antibody dilution curve demonstrated a wide range of dilutions (1:8000-1:1000), giving a stable ratio to the measured thymidine index. Lower dilutions (<1:250) produced much cytoplasmic and interstitial background staining. All single label PCNA antibody reactions were performed at a 1:4000 ratio; a 1:500 ratio was used for double immunocytochemistry.Human Tissue Preparation. Major epicardial coronary artery segments were obtained from 13 diseased human hearts removed at the time of cardiac transplantation. Five of these hearts displayed severe coronary artery disease, and 8 hearts exhibited idiopathic dilated cardiomyopathy. Tissues were fixed overnight in methyl Carnoy's fixative, paraffin embedded, and sectioned. Separate arteries were snap frozen in OCT compound (Miles) and later sectioned for the Ki-67 antibody reactions described below. Artery segments were divided into two categories: (i) diffuse intimal thickening (DIT) 4600The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 ...

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