Inflammation at the molecular interface of atherogenesis: an anthropological journey

Abstract

Despite the multifactorial nature of atherosclerosis, substantial evidence has established inflammation as an often surreptitious, yet critical and unifying driving force which promotes disease progression. To this end, research has defined molecular networks initiated by cytokines, growth factors and other pro-inflammatory molecules which promote hallmarks of atherosclerosis such as endothelial dysfunction, macrophage infiltration, LDL oxidation, cell proliferation and thrombosis. Although commonly associated with risk factors such as dyslipidemia, diabetes and hypertension, the global etiology of atherosclerosis may be alternatively attributed to underlying anthropological pressures. The agricultural, industrial and technological revolutions produced alterations in dietary, social and economic factors which have collectively exaggerated the exposure of the human genome to environmental stimuli. Furthermore, advances in sanitation, nutrition, and medicine have increased the lifespan of humans, effectively prolonging blood vessel exposure to these factors. As a result, the vasculature has become conditioned to respond to injury with what is arguably an overzealous immunological response; thus setting the stage for the prevalence of cardiovascular disease, including atherosclerotic plaque development in Western populations. Evidence suggests that each of these alterations can be linked to specific mediators in the inflammatory process. Integration of these factors with an inflammation-based hypothesis of atherosclerosis has yet to be extrapolated to observations in the realms of basic and clinical sciences and is the focus of this review.

Figure 1

ECs, macrophages (Mϕ), SMCs, platelets, and B and T cells contribute to plaque development, potentially culminating in thrombosis. Vascular events depicted here are induced by inflammatory stimuli and occur in a cyclic manner to drive atherogenesis. Anthropological stimuli interject at multiple stages of lesion formation to enhance the inflammatory process during atherosclerosis. ECM, extracellular matrix.

Figure 2

Hypothetical scheme of average life span at birth and fat intake (as percentage caloric intake) for select time periods. Data adapted from references.,,

Figure 3

Anthropological stimuli including nutritional characteristics, active versus sedentary lifestyles, socioeconomic class, and others dictate the expression profiles of our genome on two major levels. Chronically, these stimuli influence the widespread expression of genes, including the incorporation of beneficial mutations and the purging of undesirable genetic code. Acutely, these stimuli provoke a response that manifests as the genetic expression of an individual. Recent historical evidence demonstrates that changes in these stimuli have resulted in an amplified inflammatory response that collectively conditions and predisposes the vessel wall to plaque formation. Elucidation of these pathways at the genetic surface of populations, as well as individuals, will uncover multiple avenues of enhancing therapeutics, including risk stratification, lifestyle modifications, and personalized medicine, as well as the identification of inflammatory markers and molecular targets.