Published June 11 in the journal Circulation, the study explores a mechanism for enhancing TET2 (TET methylcytosine dioxygenase 2) enzymatic activity with high dose injections of ascorbic acid.
Allograft vasculopathy is a devastating complication that occurs when the immune system recognizes the blood vessels of a transplanted organ as foreign. Ascorbic acid may reduce complications that can occur after a heart transplant by increasing TET2 activity. “Our new work shows that TET2 is depleted during this immune response, leading to transplant vasculopathy,” said Kathleen Martin, PhD, the study’s senior author. “We speculated that enhancing TET2 expression and activity with vitamin C might slow the disease.”
Martin, a professor of medicine and pharmacology and co-director of the Yale Cardiovascular Research Center (YCVRC), co-authored the study with Allison Ostriker, PhD, now a scientist at Dicerna Pharmaceuticals.
The research team discovered that injecting ascorbic acid in mouse models could prevent allograft vasculopathy, a condition that limits the long-term success of heart transplantation. This vasculopathy affects almost half of transplanted hearts recipients 10 years after surgery and contributes to 30 percent of patient deaths post-transplant.
The Martin lab aims to understand the unique plasticity of vascular smooth muscle cells (VSMCs) that contributes to cardiovascular disease. This study expands the potential role of the TET2 enzyme in vascular abnormalities. Martin previously identified TET2 as a master regulator of gene expression in vascular smooth muscle cells that helps maintain a healthy blood vessel wall. In a 2017 paper in Science with researchers at Boston University School of Medicine, the lab helped demonstrate a protective role for the epigenetic modifier enzyme TET2 in atherosclerotic plaque development.
Previous clinical trials of oral ascorbic acid post-transplant have had mixed results. Martin and Ostriker theorize that high-dose ascorbic acid treatment could offer a safe and cost-effective potential therapy to prevent vascular injury due to transplant failure.
Our new work shows that TET2 is depleted during this immune response, leading to transplant vasculopathy.
Kathleen Martin, PhD
Lavanya Bellumkonda, MD, an associate professor who specializes in heart transplantation, adds that standard post-transplant protocols differ across institutions. “In general, transplant patients who are considering routine vitamin supplementation should speak to their transplant team first. This study supports the need for further investigation of how these enzymes may prevent vascular injury and coronary allograft vasculopathy in transplant recipients,” said Bellumkonda.
This study was supported by research grants from the National Institutes of Health and the American Heart Association.