Tachycardia promotes Mitochondrial DNA Damage by JNK Translocation to Mitochondria

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia that affects 5% of the population over the age of 65. The rapid and irregular pulse rates associated with AF have been reported to lead to altered hemodynamics by irregular stroke volumes and turbulent flow. Shear stress, the viscous drag force of blood flow, regulates endothelial function and is intimately related to vascular oxidative stress and inflammatory responses. We hypothesize that the irregular ventricular response associated with AF contributes to pro‐inflammatory states that lead to mitochondrial dysfunction in endothelial cells. A dynamic flow system was used to implement pulsatile flow in response to tachycardia at arterial carotid bifurcations. Human aortic endothelial cells (HAEC) were exposed pulsatile shear stress at 23±5 dyne·cm−2 at 140 beats per minute (PSS140, CL=429). PSS140 induced JNK activation at the mitochondria at 30 minutes (1.85‐fold increased compared to static, p<0.05, n=5) which as accompanied by an increased in MitoSOX Red intensities. PSS140 also increased mitochondrial DNA damage (as measured by 4,977‐bp deletion) and autophagy. Inhibition of JNK and antioxidant treatment attenuated these responses. When taken together, these findings suggest that JNK activation mediates rapid‐pulse rate induced cellular redox states which