Tripartite factors leading to molecular divergence between human and murine smooth muscle

Abstract

A large number of pre-clinical and developmental investigations involve experimental vertebrate animals, of which mice have emerged as a favored organism. Recognition of the differences between humans and mice is essential for assessment of the relevance of animal studies to humans. The primary purpose of this study was to gauge the conservation between human and mouse vascular smooth muscle cell (VSMC) proteins mined from an analysis of the Human Protein Atlas. Two comparison were made: a) immunohistochemistry for 16 proteins in brain, heart, esophagus, bladder, stomach, lung, kidney, and aorta enabled comparison between human and mouse of protein localization in VSMC and nonvascular 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 in an organ and cell-type dependent fashion. Many markers demonstrated 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 of murine experimental models.

Identification of the Genetic Basis for the Large-tailed Phenotypic Trait in Han Sheep Through Integrated mRNA and miRNA Analysis of Tail Fat Tissue Samples

“…In our identi ed DEGs, such as ADIRF (Adipogenesis Regulatory Factor) encodes a protein that is closely linked to adipocytic differentiation and development, controlling transcription activity early during the preadipocyte differentiation process [38,39]. HSD17B12 (Hydroxysteroid 17-Beta dehydrogenase 12) has been associated with suppressed adipocyte lipid accumulation, consistent with its predicted effect predicted in model system [40].…”

Brain arteriolosclerosis

“…Intriguingly, there is significant evolutionary molecular divergence (especially between rodents and humans) in vascular smooth muscle cells [113], underscoring the structural and functional uniqueness of human arterioles.…”

Concentration of non-myocyte proteins in arterial media of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

“…non-vascular tissue and across multiple species, with uncommon exceptions [24]. These proteins were independent from canonical SMC markers which were previously examined [22].…”

“…To test this, we selected probes that have been shown to react reliably against archival brain tissue and which specifically highlight SMC. In a previous study, we characterized 16 non-canonical SMC molecules in human brain arterial SMC proteins and showed that they were largely conserved in SMC of vascular and non-vascular tissue and across multiple species, with uncommon exceptions [ 24 ]. These proteins were independent from canonical SMC markers which were previously examined [ 22 ].…”

“…Candidates for the current extended screen include probes that we have curated from a large scale visual screen of the Human Protein Atlas [ 23 ] which identified a series of novel proteins that are expressed selectively in vessels (versus neuroglia) within the human brain [ 24 , 25 ]. We initially focused on the expression of 16 non-canonical SMC markers in CADASIL brain with the goal of uncovering resident vascular medial proteins that accumulate within the smooth muscle layer of diseased brain.…”