Could Atherosclerosis Originate from Defective Smooth Muscle Cell Death (Apoptosis)?

COULD ATHEROSCLEROSIS ORIGINATE FROM DEFECTIVE SMOOTH MUSCLE CELL DEATH (APOPTOSIS)? CHRISTOPHER REMBOLD* Much recent research on the origin of atherosclerosis has concentrated on the role of growth factors and hormones in vascular smooth muscle growth. Overstimulation of vascular smooth muscle with growth factors or hormones is known to induce hyperplastic and/or hypertrophic responses in both cell and organ culture [1, 2]. The resulting increase in smooth muscle mass in these culture systems results from growth originating from many progenitor smooth muscle cells, i.e., a polyclonal response. This implication clearly contradicts the finding that atherosclerosis is a oligoclonal disorder. This result was most clearly demonstrated in 1973, in glucose-6-phosphate dehydrogenase (G6PD) heterozygous women [3, 4]. G6PD is present on the X chromosome and has two isoforms. Since one of the X chromosomes is randomly inactivated during development (Lyon hypothesis), G6PD heterozygous women are mosaics as regards to these two isoforms of G6PD. Normal arterial smooth muscle has numerous small regions (with a volume estimated ofless than 0.1 mm3) that exhibit a single G6PD isoenzyme. Atherosclerotic plaques are typically composed of one to several larger regions (with a volume of 1 to 3 mm3) each exhibiting a single G6PD isoenzyme. This finding suggests that the smooth muscle cells in each of these regions originated from a single clone. After this finding was published, there was intense debate over whether atherosclerosis resulted from either hyperlipidemia [5] or clonal proliferation [6] . A search of the subsequent literature suggests that the hyperlipidemic hypothesis has been much more popular; a Medline search of "atherosclerosis" and "mosaicism" ("monoclonal" and "clonal" are not MESH headings) found only nine references between 1977 and 1993. I contend that we cannot The helpful discussions with Mike Williams and Peter Quesenberry and the support of the Lucille P. Markey Charitable Trust are gratefully acknowledged. *Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville , VA 22908© 1996 by The University of Chicago. All rights reserved. 0031-5982/96/3903-0947$01.00 Perspectives in Biology and Medicine, 39, 3 ¦ Spring 1996 | 405 ignore the evidence for a monoclonal origin of atherosclerosis; both hypotheses must be correct. An example of a known oligoclonal disorder is human follicular B-cell lymphoma. In this lymphoma, overexpression of the BCL-2 gene [7, 8] prevents programmed normal cell death, which has been termed apoptosis [9]. Affected lymphocytes fail to die after removal of growth stimuli. Subsequent growth stimulation induces proliferation of the remaining lymphocytes . Repeated cycles of nonselective growth and selective cell death select for apopototic deficient cells and result in an oligoclonal overgrowth of these abnormal cells. The victim of follicular B-cell lymphoma dies from the accumulation of these otherwise benign lymphocytes. A reasonable hypothesis is that atherosclerosis could have a pathogenesis similar to human follicular B-cell lymphoma. For atherosclerosis to develop according to this hypothesis, three factors are necessary. (1) The normalphysiology of the vascular wall is to maintain a constant wall thickness (mass) for a given load (blood pressure). If wall thickness decreases or load increases, then smooth muscle cells proliferate. If thickness increases (e.g., from inappropriate stimulated cell proliferation) or load decreases, then some cells undergo programmed cell death (apoptosis). This hypothesis is consistent with the structural theory of hypertension developed by Folkow [10]. (2)In susceptible individuals, a small number ofvascular smooth muscle cells have defective antiproliferative genes. Potential candidates are P53 and BCL-2 [H]. (3)Occasional episodes ofinappropriate growth stimulation occur. The most likely cause ofthis growth stimulation results from injury to the vascular wall [12] . According to the current hypothesis, functional or physical endothelial disruption by hypertension and/or other factors allows platelet, monocyte, and lipoprotein infiltration into the vessel wall. Local or systemic hormones/growth factors induce smooth muscle growth and migration from the media to the intima of the vessel wall. Higher plasma levels of low density lipoproteins (especially if oxidized), lipoprotein (a), and cigarette smoking enhance this process; higher high density lipoproteins retard this process. If these three factors are present, atherosclerosis would develop according to the following scenario. Multiple injuries would occur to the vascular wall over a long period (40 to 60 years). These...