Study Identifies New Potential Target for Treating Vascular Disease

Drugs that target fragile-X related protein-1 (FXR1), an mRNA-binding protein, may aid in treating vascular proliferative disease

Vascular diseases, such as stroke, peripheral vascular disease, renal failure, and myocardial infarction, remain a major cause of mortality in the US, Europe, and other parts of the world. Vascular smooth muscle cell (VSMC) activation plays a critical role in the development of several vascular diseases. A recent study published in The American Journal of Pathology has shown that the absence of fragile-X related protein-1 (FXR1) leads to slower VSMC proliferation, increased senescence, and reduced development of scar tissue (neointima). The findings suggest that drugs targeting FXR1 could be effective in treating vascular proliferative diseases.

Lead investigator, Michael V. Autieri, PhD from the Department of Cardiovascular Sciences at Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA, stated that their lab had previously observed an increase in expression of FXR1, an RNA binding protein that enhances muscle and seems to reduce inflammatory transcripts, in injured arteries and plaque VSMC in human aortas. However, the team had not yet investigated the impact of FXR1 expression on the vascular response to injury in an appropriate animal model of vascular disease. Therefore, they designed the current study to address this gap in knowledge.

To gain further insights into the effects of the lack of FXR1, the researchers conducted RNA-sequencing on human VSMCs where FXR1 was depleted. The findings indicate that FXR1 plays a role in stabilizing a cluster of transcripts that regulate the cell cycle, primarily linked with cell division and proliferation. Additionally, the study revealed an increase in the levels of beta galactosidase and gamma H2AX, which are molecules that signify cellular senescence.

Next, to understand how the absence of FXR1 would affect vascular occlusive disease, they developed a mouse model to specifically deplete FXR1 in the smooth muscles upon drug induction. The mice were subjected to carotid ligation, which is a model of vascular stenosis. Drug-induced depletion of FXR1 in smooth muscle cells protected the mice against neointima formation following injury. Injured arteries had a gene expression profile similar to human VSMC following FXR1 knockdown.

Dr. Autieri commented that these findings provide the first evidence suggesting that FXR1 not only destabilizes inflammatory transcripts but also stabilizes genes related to the cell cycle in VSMCs. The absence of FXR1 induces a senescent phenotype, indicating that FXR1 may play a crucial role in regulating the stability of mRNA related to proliferation in VSMCs, contributing to the development of vascular diseases.

The researchers were surprised to discover that FXR1, which is commonly known as an RNA-binding protein that destabilizes transcripts, was found to stabilize this particular group of transcripts. Furthermore, the research team did not anticipate such a striking outcome when they created the knockout mouse model for the study.

Dr. Autieri concluded that as their study showed that the absence of FXR1 leads to a reduction in VSMC proliferation and induces a senescent phenotype, drugs targeting FXR1 could be potentially used as therapies to combat vascular proliferative diseases such as atherosclerosis, restenosis, hypertension, and abdominal aortic aneurysm. Considering the global rise in cardiovascular diseases among the aging and increasingly sedentary population, it is vital to investigate genes and targets that may be exploited to influence disease pathology.

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