Callie S. Kwartler, PhD
Assistant Professor, Department of Internal Medicine, The University of Texas Health Science Center at Houston

“Epigenetic Control of Smooth Muscle Differentiation: Insights from Smooth Muscle Dysfunction Syndrome”

Abstract

Heterozygous ACTA2 p.R179 pathogenic variants cause Smooth Muscle Dysfunction Syndrome. ACTA2 encodes smooth muscle α-actin (SMA), and the p.R179 variant disrupts nuclear localization of SMA, leading to incomplete differentiation of smooth muscle cells (SMCs). SMCs from a conditional knock-in mouse model (Acta2R179C/+) are incompletely differentiated, leading to enhanced SMC migration and proliferation that may drive the occlusive lesions. Furthermore, Acta2R179C/+ SMCs have increased glycolysis and reduced oxidative respiration on Seahorse analyses. Nicotinamide riboside (NR) treatment restores oxidative respiration through increased complex I activity in Acta2R179C/+ SMCs, and surprisingly also increases SMC differentiation and decreases migration. Acta2R179C/+ mice and littermate controls were subjected to carotid artery ligation (CAL), and 25% of Acta2R179C/+ mice died due to strokes while all control mice survived (p<0.01). Surviving Acta2R179C/+ mice have signs of hypoxic brain injury and neuron death at three days post-CAL and persistent occlusive carotid artery lesions at 21 days post-CAL. Treatment of female Acta2R179C/+ mice with NR reduces death (Kaplan-Meier p=0.02) and resolves persistent lesions (p=0.05) in Acta2R179C/+ mice after CAL. The mechanism by which NR treatment increases SMC differentiation is not intuitive. Our data suggests that high glycolytic flux in Acta2R179C/+SMCs leads to increased accumulation of 2-hydroxygluterate (2-HG), which has been previously shown to inhibit TET2, a master regulator of SMC differentiation. NR reduces glycolysis and 2-HG, increasing TET2 activity and driving increased SMC identity.