Long noncoding RNA LEENE promotes angiogenesis and ischemic recovery in diabetes models.
Publication Year:
2023
PubMed ID:
36512424
Public Summary:
Reduced blood vessel growth, or angiogenesis, in people with diabetes is a major factor in ischemic diseases like peripheral arterial disease, where blood flow to tissues is blocked. This study identifies a molecule called LEENE, a type of RNA that helps regulate blood vessel growth, as important in how tissues respond to low blood flow in diabetic conditions. We found that LEENE levels were lower in diabetes, both in cells that line blood vessels and in mouse and human tissues. When LEENE was inhibited, blood vessel cells lost their ability to form new blood vessels effectively.
In diabetic mice lacking LEENE, blood flow recovery after reduced circulation to the limbs was poor. However, when we reintroduced human LEENE, it restored blood flow and gene activity related to vessel growth in these mice. We also explored how LEENE works, finding it helps activate genes essential for blood vessel growth, likely by interacting with proteins involved in turning genes on.
Our findings show LEENE plays a vital role in blood vessel health, and boosting its function could be a potential approach for treating ischemic diseases by helping tissues recover blood flow and heal.
Scientific Abstract:
Impaired angiogenesis in diabetes is a key process contributing to ischemic diseases such as peripheral arterial disease. Epigenetic mechanisms, including those mediated by long noncoding RNAs (lncRNAs), are crucial links connecting diabetes and the related chronic tissue ischemia. Here we identify the lncRNA that enhances endothelial nitric oxide synthase (eNOS) expression (LEENE) as a regulator of angiogenesis and ischemic response. LEENE expression was decreased in diabetic conditions in cultured endothelial cells (ECs), mouse hind limb muscles, and human arteries. Inhibition of LEENE in human microvascular ECs reduced their angiogenic capacity with a dysregulated angiogenic gene program. Diabetic mice deficient in Leene demonstrated impaired angiogenesis and perfusion following hind limb ischemia. Importantly, overexpression of human LEENE rescued the impaired ischemic response in Leene-knockout mice at tissue functional and single-cell transcriptomic levels. Mechanistically, LEENE RNA promoted transcription of proangiogenic genes in ECs, such as KDR (encoding VEGFR2) and NOS3 (encoding eNOS), potentially by interacting with LEO1, a key component of the RNA polymerase II-associated factor complex and MYC, a crucial transcription factor for angiogenesis. Taken together, our findings demonstrate an essential role for LEENE in the regulation of angiogenesis and tissue perfusion. Functional enhancement of LEENE to restore angiogenesis for tissue repair and regeneration may represent a potential strategy to tackle ischemic vascular diseases.
