Supplementary MaterialsS1 Fig: Supplemental data 1
November 9, 2020
Supplementary MaterialsS1 Fig: Supplemental data 1. 16 proteins in brain, heart, esophagus, bladder, stomach, lung, kidney, and aorta enabled comparison between human and mouse of protein localization in VSMC and non-vascular SMC; and b) multi-species primary protein sequence analysis of an expanded set vascular molecules enabled comparison between VSMC sequences among vertebrate species. In total, three dimensions of diversity were uncovered. First, a significant number of factors show human/mouse differences in cellular expression; these differences occurred in both VSMC and non-vascular SMC BPTES in an organ and cell-type dependent fashion. Many markers exhibited notable cell-to-cell and regional heterogeneity in VSMC of the aorta and non-vascular SMC of the esophagus, bladder, and stomach. Second, species specificity can arise by genetic deletions as exemplified by the human protein adipogenesis regulatory factor (ADIRF), which is not present due to a large sequence gap in mice. Third, we describe significant cross-species protein sequence divergence in selected VSMC proteins which may result in altered orthologue function. In a sample of 346 vascular molecules, 15% demonstrate incomplete vertebrate species gene conservation. Divergence of predicted human/mouse VSMC protein sequences is higher than for endothelial proteins in all species examined. In the future, each of these three cross-species differences could be neutralized using gene manipulation, resulting in improved translational potential Rabbit Polyclonal to Tyrosine Hydroxylase of murine experimental models. Introduction The importance of the vascular system in physiology of all organs and in human disease has driven efforts to understand blood vessels at the molecular level. For example, endothelial cell (EC) expression profiles have been described in detail on a global basis in numerous transcriptome and proteome wide efforts [1C4]. However, comparable in depth understanding of proteins in vascular easy muscle cells (VSMC) is usually less well-developed. This knowledge-gap prompted a recent study of global protein expression in humans that gave equal emphasis to brain VSMC and EC proteins and resulted in identification of a panel of new VSMC BPTES molecules in brain . The functions of these newly identified VSMC proteins remain largely unknown, but the scope of this endeavor requires additional characterization to enable prioritization of future functional analysis. Current translational studies rely heavily on mouse models of disease that enable delineation of molecular mechanism. However, many studies of vascular diseases have failed to demonstrate clinical efficacy of treatments BPTES that proved effective in mice and other model organisms. For example, in cerebrovascular disease, human clinical trials have not succeeded using brokers validated in mouse models [5C7]. Furthermore, CADASIL, the most common inherited cause of stroke and vascular dementia and a result of failure of VSMC, is BPTES not recapitulated in mice harboring gene mutations found in patients [8C10]. In other fields as well, only a minority of mouse studies yield successful human clinical applications; in cancer, the translational success rate from mouse to human is usually 10% . In gastrointestinal disorders, drug screening for anti-gastrosecretory drugs using rodents led to agents that were ineffective in people . The challenges BPTES of building bridges that connect mouse models to human pathology suggest potential dissimilarities between mouse and human blood vessels. Transcriptome analysis has exhibited divergence between mouse and human RNA expression patterns in tissues and organs ; however, little is known at cellular resolution, and few studies focus on protein differences. Several recent studies suggest molecular differences between human and.