Abstract
Autophagy is a catabolic process for cell survival in times of stress. However, dysregulation for this process can have detrimental effects on cell survival. In fact, insufficient autophagy has been proposed as a mechanism of apoptosis due to the accumulation of proteins and defective organelles. We have observed that spontaneously hypertensive rats (SHR) have elevated circulating levels of the damage‐associated molecular pattern mitochondrial DNA (mtDNA), diminished activity for the enzymes responsible for its degradation, deoxyribonuclease (DNase) I and II, and these novel phenotypes contribute to the activation of Toll‐like receptor (TLR)9. Therefore, we hypothesized that expression of representative proteins associated with autophagy are decreased in SHR and that TLR9 activation contributes to this down regulation. We observed decreased expression of autophagic proteins in the aorta of SHR (Beclin‐1, ATG5, and LC3‐I and ‐II) (p<0.05 vs. WKY). Moreover, in vivo treatment of normotensive rats with a synthetic TLR9 agonist (ODN2395; 0.1 μg/i.p.), increased systolic blood pressure (mmHg, Veh: 141±3 vs. ODN2395: 154±3, p<0.05) and decreased the expression of ubiquitin‐like protein and autophagosomal marker LC3‐II in both resistance arteries and the aorta (p<0.05 vs. Vehicle). These results suggest that stimulation of TLR9 may be a contributing mechanism for the reduction in the autophagic machinery observed in SHR. Therefore, targeted inhibition of mtDNA and/or TLR9 could prevent the dysregulation of autophagy in hypertension.
Published Version
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