Replacing Magic Bullets With Beneficial Pleiotropy in Atherosclerosis
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Atherosclerosis is a complex process, involving the interaction of multiple cell types and processes. The next generation of therapeutics needs to focus on pathways exerting multiple beneficial effects on multiple processes in multiple cell types.
Theories of atherogenesis have evolved over the decades, with established concepts often being incorporated into new theories. This is the natural progression of science; the old theories are not necessarily discredited—in many cases, they explained what was known at the time—but rather new models emerge that incorporate new knowledge and change the emphasis placed on particular processes. Thus, “Time obliterates the fictions of opinion and confirms the decisions of nature” (Marcus Tullius Cicero). Each model is presented as the state of the art, and each is embraced by a new generation of opinion leaders. What has not changed, however, is the hope that each new theory of atherogenesis will result in a new magic bullet, a pharmacological ideal of a drug able to selectively target a disease without other effects on the body, originally defined by Paul Ehrlich for a drug for antibacterial therapy.
Individual cell types, processes, and molecules have been sequentially implicated in theories of atherogenesis, such that the whole process can become viewed as driven by their dysfunction, and thus become targets for magic bullets. For example, endothelial cells, smooth muscle cells, macrophages, T-lymphocytes, bone marrow–derived stem cells, or endogenous vessel wall–derived stem cells; processes such as lipid insudation, inflammation, cell proliferation, cell migration, cell death, or matrix breakdown; or the latest gene implicated by basic science or genome-wide association studies have all been presented as fundamental and necessary to atherosclerosis. As researchers, we test the validity of this concept for each cell type, process or molecule by increasing or decreasing its abundance, activity or expression, and determine whether it increases or …