Abstract P116: Inhibition of Ang II-Induced Mitochondrial Fission and Endoplasmic Reticulum Stress Attenuates Protein Aggregate Accumulation, Inflammation, and Senescence in Vascular Smooth Muscle Cells

Aging is a non-modifiable risk factor for most cardiovascular diseases (CVDs) including hypertension and abdominal aortic aneurysms (AAA). As much as 14-year difference was noted in vascular aging assessed by arterial stiffness in healthy middle age human population, suggesting that premature vascular aging is a promising therapeutic target to combat against CVD. The molecular mechanisms involved in Ang II induction of premature vascular aging and how these contribute to CVD development are poorly understood. The objective of this study was to elucidate involvement of mitochondria and endoplasmic reticulum (ER) dynamics in Ang II-induced senescence in vascular smooth muscle cells (VSMCs), and how these contribute to CVDs. Ang II is known to promote mitochondrial fission and increases oxidative stress, and subsequent ER stress. Thus, chronic activation of Ang II signaling has been reported here to cause proteotoxicity due to accumulation of protein aggregates. Sodium 4-phenylbutyrate (PBA) increases ER folding capacity to restore proper protein folding and attenuate activation of UPR. Our in vitro data show Ang II enhances protein aggregate formation and PBA pretreatment alleviates their cellular accumulation in both size and number. Treatment of rat aortic VSMCs with 4-PBA or mitochondrial fission inhibitor mdivi1 mitigates Ang II induced VSMC senescence, detected by 4% (p=0.04) and 5% (p=0.02) reduction in senescence-associated β galactosidase (SA-β gal) positive cells, respectively. Ang II induced VSMC inflammation was monitored by THP-1 adhesion assay with a 1.87 fold increase in leukocyte adhesion (p=0.017), which was attenuated by PBA. In vivo , male C57/B6 mice infused with Ang II (4 weeks) with beta-aminopropionitrile (drinking water) (AAA model) +/- mdivi1 25 mg/kg IP 3x per week), which reduced AAA development, ER stress, leukocyte infiltration, and senescence. Taken together, these data represent a unique signaling pathway whereby Ang II-induced mitochondrial fission contributes to disturbed proteostasis, culminating in VSMC senescence and vascular inflamm-aging. The elucidation of Ang II contribution to irreversible vascular senescence sheds light on potential alternative therapeutic targets for high-risk CVD populations.