Postdoctoral Research Fellow
Fellow or Postdoc
Madhur Sachan*, Shruti Rawal, Winona Wu, Camila Vaz, AKM Wara, Michael McCoy, Henry Cheng, Daniel Perez-Cremades, Phil P. Goodney, Mark A. Creager, Marc S. Sabatine, Marc P. Bonaca, and Mark W. Feinberg
Mark W. Feinberg
Critical limb ischemia (CLI) is an advanced Peripheral Artery Disease (PAD) that results in restricted blood flow to the lower extremities and is often associated with diabetes. However, the implications of microRNAs (miRNAs) in diabetic CLI remain poorly elucidated. Consequently, by overlapping plasma miRNA sequencing in PAD patients that develop CLI with a suitable mouse model, miRNAs were identified in the diabetic CLI progression. We describe miR-1282, a previously uninvestigated miRNA that was the highest upregulated in high-risk diabetic CLI human subjects. We first uncover a mouse ortholog of human miR-1282, a cis-antisense miRNA, that strongly inhibits the expression of SERF2, a protein-coding gene located on the opposite DNA strand. SERF2 can promote protein aggregation; however, its function largely known; whereas miR-1282 is a hypoxia-induced endothelial-enriched miRNA, and its expression inversely correlates with SERF2 expression in endothelial cells. In vitro studies indicate that miR-1282 overexpression or SERF2 knockdown promotes endothelial angiogenesis, reduces apoptosis, and inhibits protein aggregation. In vivo, we found that miR-1282 overexpression improves blood flow recovery and induces angiogenesis in db/db mice following femoral artery ligation. Together, this study shows that miR-1282 and SERF2 might form a novel cis-antisense axis to regulate angiogenesis and proteostasis in diabetic CLI.
In peripheral artery disease (PAD), the narrowed blood vessels limit the blood flow to the legs. This happens because there are fatty deposits inside these vessels. People with PAD often feel pain in their legs when they walk or exercise. Some patients experience constant rest pain and an increased risk of losing their legs. This severe situation is known as critical limb ischemia (CLI). People with type 2 diabetes are at a higher risk for PAD and CLI, but we are unsure why. Therefore, we looked at the changes in tiny messengers called microRNAs in the blood of people with PAD and diabetes. These microRNAs can help our body work well. We overlapped these changes with a mouse model. We found one specific microRNA that stands out and is the focus of our study. We then checked if this microRNA could control the blood flow in the mouse model. If we can figure out how this microRNA works, it may offer in the future a new approach to improve blood flow in legs of patients with PAD.