TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy

Area of Science:

• Transplant immunology
• Vascular biology
• Epigenetics

Background:

• Coronary allograft vasculopathy (CAV) is a leading cause of heart transplant failure, characterized by intimal thickening and limited coronary blood flow.
• Vascular smooth muscle cell (VSMC) phenotypic changes are central to CAV development, but the underlying epigenetic mechanisms are poorly understood.
• TET methylcytosine dioxygenase 2 (TET2) is an epigenetic regulator of VSMC phenotype, yet its role in CAV progression remains unelucidated.

Purpose of the Study:

• To investigate the role of TET2 in the pathogenesis of coronary allograft vasculopathy (CAV).
• To determine the impact of interferon-gamma (IFNγ) on TET2 expression and VSMC phenotype.
• To explore the therapeutic potential of enhancing TET2 activity in preventing transplant vasculopathy.

Main Methods:

• Assessed TET2 expression and activity in human CAV and renal transplant samples.
• Utilized a murine aortic graft model of graft arteriopathy (GA) and wire-induced restenosis model.
• Employed in vitro studies with human and murine VSMCs, including knockdown, overexpression, and transcriptomic analyses, to assess responses to IFNγ.
• Investigated the effect of ascorbic acid on VSMC apoptosis and intimal thickening in vivo.

Main Results:

• TET2 expression and activity were reduced in human and murine transplant vasculopathy models, correlating with IFNγ presence.
• IFNγ repressed TET2, inducing an activated VSMC phenotype, while TET2 depletion mimicked IFNγ effects.
• VSMC-specific TET2 deficiency increased apoptosis and intimal thickening in graft and restenosis models.
• Systemic administration of ascorbic acid enhanced TET2 activity, reducing VSMC apoptosis and intimal thickening in GA.

Conclusions:

• TET2 is downregulated in CAV and GA, potentially mediated by IFNγ, and protects VSMCs from apoptosis.
• TET2 activity is crucial for maintaining VSMC homeostasis and preventing transplant-associated intimal thickening.
• Enhancing TET2 activity, for instance with ascorbic acid, presents a promising therapeutic strategy to mitigate CAV progression.