Vascular diseases, such as stroke, renal failure, peripheral vascular disease, and myocardial infarction, are responsible for one third of mortalities in the United States, Europe, and developing countries, according to the World Health Organization (2021). Vascular smooth muscle cell (VSMC) activation is critical to the development of several vascular diseases. Researchers have published a novel study in The American Journal of Pathology, presented by Elsevier, which shows that when fragile-X related protein-1 (FXR1) is absent, VSMC proliferate more slowly, become senescent, and reduce the development of scar tissue (neointima). Therefore, drugs targeting FXR1 might treat vascular proliferative diseases.
Previously, Michael V. Autieri, Ph.D., lead investigator at the Lewis Katz School of Medicine at Temple University in Philadelphia, PA, USA, and his team reported that FXR1 expression increases in injured human aortas and plaque VSMC, a muscle-enhanced RNA binding protein that has the potential to decrease inflammatory transcripts. However, the role of FXR1 in vascular injury responses had not yet been studied in a relevant animal model of vascular disease. To extend their understanding of the absence of FXR1’s impact, investigators conducted RNA sequencing on FXR1-depleted human VSMCs. Their results suggest that FXR1 appears to stabilise a group of transcripts involved in controlling the cell cycle, most of which are associated with proliferation and cell division. They also observed an increase in beta galactosidase and gamma H2AX, molecules indicative of cell senescence.
Next, to understand how the absence of FXR1 would affect vascular occlusive disease, they created a mouse model to specifically deplete FXR1 in the smooth muscles upon drug induction. They subjected the mice to carotid ligation, which models vascular stenosis. The drug-induced depletion of FXR1 in smooth muscle cells protected the mice from neointima formation following injury. Injured arteries had a gene expression profile closely resembling that of human VSMCs following FXR1 knockdown.
Dr Autieri stated, “These results are the first to suggest that in addition to destabilisation of inflammatory transcripts, FXR1 may stabilize genes related to the cell cycle in VSMC, and the absence of FXR1 results in the induction of a senescent phenotype. This supports the theory that FXR1 can regulate the stability of proliferative mRNA in VSMC, contributing to vascular disease.” The researchers were surprised to find that while FXR1 is typically regarded as an RNA-binding protein that destabilises transcripts, it stabilised this group of transcripts. Additionally, while they expected to see a difference in the knockout mouse phenotype compared to controls, they did not expect such a dramatic result.
Dr Autieri concluded, “Since we have discovered that in the absence of FXR1, VSMCs substantially reduce proliferation and become senescent, targeting FXR1 drugs may have implications for modalities to combat vascular proliferative diseases, including hypertension, restenosis, atherosclerosis, and abdominal aortic aneurysm. Given the global increase in cardiovascular diseases in an ageing and increasingly sedentary population, it is essential to investigate potential genes and targets that might be exploited to impact disease pathology.”
