Misbah Aziz

PhD student, Diabetes

Supervisors: Professor Karin Jandeleit-Dahm, Dr Waheed Khan

What I’m Working On: A New Hope for Diabetic Heart Disease

Two-thirds of diabetes-related deaths are due to cardiovascular disease. Normally, the cells that line the blood vessels (endothelial cells) keep everything running smoothly, like workers maintaining a highway. But in diabetes, something goes off beat: these endothelial cells undergo a transformation known as the endothelial-to-mesenchymal transition, or EndoMT. This can lead to the buildup of plaques in the blood vessels, making them a ticking time bomb for heart disease.

The hidden culprit for this cellular identity crisis is the EZH2 protein - an enzyme that is part of the cells’ epigenetic machinery. It does not alter the DNA sequence, but acts like adding the sticky note, or in this case a “methyl tag” that silences several protective genes, fuelling disease.

My research focused on targeting this overactive “silencer.” the EZH2 protein, by using a small molecular inhibitor called GSK-126, which acts like a mute button for EZH2. This drug doesn't just shut down EZH2 randomly. It specifically targets the methyl-binding domain-part of EZH2 that's responsible for recognizing and spreading these silencing marks to nip the evil in the bud and thus attenuate EndMT and atherosclerosis in pre-clinical studies.

The impact of EZH2 silencing is not just about one protein, but it is about interrupting a domino effect, and switching on protective genes. In my studies, we aim to fight against diabetic heart disease by silencing the silencer EZH2 with the epigenetic drug GSK-126 and to give our blood vessels a chance to stay healthy.

“Epigenetic mechanisms in diabetes- associated atherosclerosis are a novel concept,” says Misbah’s supervisor, Professor Karin Jandeleit-Dahm. “By targeting the silencer EZH2, we protect the shutdown of atheroprotective genes, thereby rescuing the cells in the vascular wall undergoing an identity crisis. Targeting these epigenetic pathways in this way has the potential to rescue atherosclerosis development in the clinic.

“By targeting the silencer EZH2, we protect the shutdown of atheroprotective genes, thereby rescuing the cells in the vascular wall undergoing an identity crisis. Targeting these epigenetic pathways in this way has the potential to rescue atherosclerosis development in the clinic.”

- Professor Karin Jandeleit-Dahm.